Inhibitory chimeric antigen receptors

ABSTRACT

The invention relates to an inhibitory chimeric antigen receptor (N-CAR) comprising an extracellular domain comprising an antigen binding domain, a transmembrane domain, and, an intracellular domain wherein the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TX 1 YX 2 X 3 X 4 , wherein X 1  is an amino acid X 2  is an amino acid X 3  is an amino acid and X 4  is V or

FIELD OF THE INVENTION

The invention relates to negative T-cell signal inducing chimeric antigen receptor (N-CAR or ICAR) and to T-cells comprising such N-CAR as well as a positive T-cell signal inducing CAR (P-CAR) as well as their use in therapy.

BACKGROUND

T-cell therapies based on redirected T-cell targeting using chimeric antigen receptor (CAR) are beginning to show great promise in the clinic, particularly in the oncology setting (see Hutchinson L., Nat Rev Clin Oncol. 2014 Oct. 28; Lee D W et al., Lancet. 2014 Oct. 10. pii: S0140-6736(14)61403-3 or Grupp S A et al., N Engl J Med. 2013 Apr. 18; 368(16):1509-18). Given the growing enthusiasm of the field, there is a significant effort being made to identify appropriate targets for CAR T-cell therapy. Given the potency of such therapeutics, the field's ability to identify novel targets for such therapy is hindered by concerns about on-target off-tissue (meaning off-tumor) activity. Such events not only mitigate efficacy but also present tremendous safety challenges as demonstrated by recent clinical events (see Morgan R A et al., Mol Ther. 2010 April; 18(4):843-51; Morgan R A et al., J Immunother. 2013 Feb.; 36(2):133-51 or Linette G P et al., Blood. 2013 Aug. 8; 122(6):863-71). Clinical approaches to mitigate these safety concerns while effective also act directly or indirectly on the infused CAR T-cell therapeutic entities.

In order to address these safety issues pertaining to on-target off-tissue activity of CAR T-cells, and expand the target space amenable to this mode of therapeutics, there is growing emphasis in creating logic gates to modulate T-cell signaling (see Federov V D et al., Sci Transl Med. 2013 Dec. 11; 5(215):215ra172).

One such approach involves using a NOT gate, wherein the T-cell expresses two or more CARs on its cell surface. CARs that provide positive T-cell signals (P-CARs) bind to tumor antigens to enable T-cell activation and/or proliferation and/or cytokine secretion, and/or cytotoxicity mediated by CD3zeta or other immunoreceptor tyrosine-based activation motif (ITAM) containing motifs; while CARs that provide a negative T-cell signal (N-CARs) bind to the off-tissue antigens and attenuate or abrogate the positive signals.

Therefore under the on-tissue (on-tumor) scenario the T-cell only receives the P-CAR signal and subsequent activation and cytotoxicity and in the off-tissue (off-tumor) scenario the T-cell receives both the P-CAR and N-CAR signals, whereby the latter attenuates or terminates downstream signaling leading to impaired or no activation and cytotoxicity.

Therefore, there is a need for negative or inhibitory CAR (N-CAR) that can be used to generate a negative signal suitable to prevent off target activation of P-CAR T-cells (T-cells comprising a P-CAR). It would be an additional benefit if such negative signal is short-termed, reversible and sufficient to attenuate or prevent on-target off-tissue activity of CAR T-cells comprising such N-CAR.

DETAILED DESCRIPTION OF THE INVENTION

General Techniques

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995).

Definitions

The following terms, unless otherwise indicated, shall be understood to have the following meanings: the term “isolated molecule” as referring to a molecule (where the molecule is, for example, a polypeptide, a polynucleotide, or an antibody) that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is substantially free of other molecules from the same source, e.g., species, cell from which it is expressed, library, etc., (3) is expressed by a cell from a different species, or (4) does not occur in nature. Thus, a molecule that is chemically synthesized, or expressed in a cellular system different from the system from which it naturally originates, will be “isolated” from its naturally associated components. A molecule also may be rendered substantially free of naturally associated components by isolation, using purification techniques well known in the art. Molecule purity or homogeneity may be assayed by a number of means well known in the art. For example, the purity of a polypeptide sample may be assayed using polyacrylamide gel electrophoresis and staining of the gel to visualize the polypeptide using techniques well known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means well known in the art for purification.

An “antibody” is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site. Antigen binding portions include, for example, Fab, Fab′, F(ab′)2, Fd, Fv, domain antibodies (dAbs, e.g., shark and camelid antibodies), fragments including complementarity determining regions (CDRs), single chain variable fragment antibodies (scFv), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity determining regions (CDRs) also known as hypervariable regions, and contribute to the formation of the antigen binding site of antibodies. If variants of a subject variable region are desired, particularly with substitution in amino acid residues outside of a CDR region (e.g., in the framework region), appropriate amino acid substitution, preferably, conservative amino acid substitution, can be identified by comparing the subject variable region to the variable regions of other antibodies which contain CDR1 and CDR2 sequences in the same canonincal class as the subject variable region (Chothia and Lesk, J Mol Biol 196(4): 901-917, 1987).

In certain embodiments, definitive delineation of a CDR and identification of residues comprising the binding site of an antibody is accomplished by solving the structure of the antibody and/or solving the structure of the antibody-ligand complex. In certain embodiments, that can be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition, the contact definition, and the conformational definition.

The Kabat definition is a standard for numbering the residues in an antibody and is typically used to identify CDR regions. See, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account positions of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196: 901-17; Chothia et al., 1989, Nature, 342: 877-83. The AbM definition uses an integrated suite of computer programs produced by Oxford Molecular Group that model antibody structure. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; “AbM™, A Computer Program for Modeling Variable Regions of Antibodies,” Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from positive sequence using a combination of knowledge databases and ab initio methods, such as those described by Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. The contact definition is based on an analysis of the available complex crystal structures. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs may be defined in accordance with any of Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.

As known in the art, a “constant region” of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.

As used herein, “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or may be made by recombinant DNA methods such as described in U.S. Pat. No. 4,816,567. The monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCafferty et al., 1990, Nature 348:552-554, for example. As used herein, “humanized” antibody refers to forms of non-human (e.g. murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin. Preferably, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a CDR of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. The humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance.

A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen binding residues.

The term “chimeric antibody” is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

The term “epitope” refers to that portion of a molecule capable of being recognized by and bound by an antibody at one or more of the antibody's antigen-binding regions. Epitopes often consist of a surface grouping of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics. In some embodiments, the epitope can be a protein epitope. Protein epitopes can be linear or conformational. In a linear epitope, all of the points of interaction between the protein and the interacting molecule (such as an antibody) occur linearly along the positive amino acid sequence of the protein. A “nonlinear epitope” or “conformational epitope” comprises noncontiguous polypeptides (or amino acids) within the antigenic protein to which an antibody specific to the epitope binds. The term “antigenic epitope” as used herein, is defined as a portion of an antigen to which an antibody can specifically bind as determined by any method well known in the art, for example, by conventional immunoassays. Once a desired epitope on an antigen is determined, it is possible to generate antibodies to that epitope, e.g., using the techniques described in the present specification. Alternatively, during the discovery process, the generation and characterization of antibodies may elucidate information about desirable epitopes. From this information, it is then possible to competitively screen antibodies for binding to the same epitope. An approach to achieve this is to conduct competition and cross-competition studies to find antibodies that compete or cross-compete with one another for binding to the antigen. The term “signaling domain” refers to the functional portion of a protein which acts by transmitting information within the cell to regulate cellular activity via defined signaling pathways by generating second messengers or functioning as effectors by responding to such messengers.

The term “off-tissue antigen” (or off-tumor antigen) refers to an antigen which is present on non-tumor tissue and not present on the tumor of interest (tumor to be treated by the cells of the invention comprising a P-CAR directed to a tumor antigen and a N-CAR directed to an off-tissue antigen), or only present on the tumor of interest at much lower levels compared to levels of tumor antigen (i.e. the antigen present on the tumor of interest and targeted by the P-CAR).

The term “anti-tumor effect” refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, decrease in tumor cell proliferation, decrease in tumor cell survival, or amelioration of various physiological symptoms associated with the cancerous condition. An “anti-tumor effect” can also be manifested by the ability of the cells of the invention in prevention of the occurrence of tumor in the first place.

The term “autologous” refers to any material derived from the same individual to whom it is later to be re-introduced into the individual.

The term “allogeneic” refers to any material derived from a different animal of the same species as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some aspects, allogeneic material from individuals of the same species may be sufficiently unlike genetically to interact antigenically

The term “xenogeneic” refers to a graft derived from an animal of a different species.

The term “cancer” refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cell cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and the like.

The term “conservative sequence modifications” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antibody fragment of the invention by standard techniques known in the art, such as site- directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within a CAR of the invention can be replaced with other amino acid residues from the same side chain family and the altered CAR can be tested using the functional assays described herein.

In some embodiments, the “fragment” of a sequence of amino acids is shorter than said sequence of amino acid. In some embodiments, the fragment of a sequence of amino acids is at least 1%, 5% 10%, 20%, 40%, 50%, 60%, 70%, 80% or 90% shorter than said sequence of amino acids. In some embodiments, the fragment of a sequence of amino acids is shorter by at least 1, 5, 10, 20, 50, 100, 200, 300 amino acids as compared to said sequence of amino acids.

Unless otherwise specified, the left to right orientation of amino acid sequences or formula representing amino acid sequences are disclosed using the conventional left to right orientation N-Term to C-term.

N-terminal flanking region of a domain refers to the sequence of amino acid which is directly adjacent to the N-terminal amino acid of said domain. C-terminal flanking region of a domain refers to the sequence of amino acid which is directly adjacent to the C-terminal amino acid of said domain. For example, in the sequence seq1-ITIM-seq2, seq1 is the N-terminal flanking region of the ITIM intracellular domain and seq2 N-terminal flanking region of the ITIM intracellular domain. In another example, the naturally occurring N-terminal flanking region of ITIM.*ITSM intracellular domains is the sequence of amino acid which is directly adjacent to the N-terminal amino acid of the ITIM motif of the ITIM.*ITSM intracellular domain. In another example, the naturally occurring C-terminal flanking region of ITIM.*ITSM intracellular domain is the sequence of amino acid which is directly adjacent to the C-terminal amino acid of the ITSM motif of the ITIM.*ITSM intracellular domain.

In another example, the naturally occurring N-terminal flanking region of an ITIM only intracellular domain is the sequence of amino acid which is directly adjacent to the N-terminal amino acid of the ITIM of the ITIM only intracellular domain. In another example, the naturally occurring C-terminal flanking region of an ITIM only intracellular domain is the sequence of amino acid which is directly adjacent to the C-terminal amino acid of the ITIM of the ITIM only intracellular domain.

In another example, the naturally occurring N-terminal flanking region of an ITSM only intracellular domain is the sequence of amino acid which is directly adjacent to the N-terminal amino acid of the ITSM of the ITSM only intracellular domain. In another example, the naturally occurring C-terminal flanking region of an ITSM only intracellular domain is the sequence of amino acid which is directly adjacent to the C-terminal amino acid of the ITSM of the ITSM only intracellular domain.

The term “stimulation,” refers to a positive response induced by binding of a stimulatory molecule (e.g., a TCR/CD3 complex) with its cognate ligand thereby mediating a signal transduction event, such as, but not limited to, signal transduction via the TCR/CD3 complex. Stimulation can mediate altered expression of certain molecules, such as downregulation of TGF-β, and/or reorganization of cytoskeletal structures, and the like.

The term “antigen presenting cell” or “APC” refers to an immune system cell such as an accessory cell (e.g., a B-cell, a dendritic cell, and the like) that displays a foreign antigen complexed with major histocompatibility complexes (MHC's) on its surface. T-cells may recognize these complexes using their T-cell receptors (TCRs). APCs process antigens and present them to T-cells.

An “intracellular signaling domain,” as the term is used herein, refers to an intracellular portion of a molecule.

The term “encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene, cDNA, or RNA, encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or a RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).

The term “effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result.

The term “endogenous” refers to any material from or produced inside an organism, cell, tissue or system.

The term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue or system.

The term “expression” refers to the transcription and/or translation of a particular nucleotide sequence driven by a promoter.

The term “transfer vector” refers to a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “transfer vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to further include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, a polylysine compound, liposome, and the like. Examples of viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like.

The term “expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, including cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.

The term “lentivirus” refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.

The term “lentiviral vector” refers to a vector derived from at least a portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). Other examples of lentivirus vectors that may be used in the clinic, include but are not limited to, e.g., the LENTIVECTOR® gene delivery technology from Oxford BioMedica, the LENTIMAX™ vector system from Lentigen and the like. Nonclinical types of lentiviral vectors are also available and would be known to one skilled in the art.

The term “homologous” or “identity” refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position. The homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 of 10), are matched or homologous, the two sequences are 90% homologous.

The term “operably linked” or “transcriptional control” refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences can be contiguous with each other and, e.g., where necessary to join two protein coding regions, are in the same reading frame.

The terms “polypeptide”, “oligopeptide”, “peptide” and “protein” are used interchangeably herein to refer to chains of amino acids of any length. The chain may be linear or branched, it may comprise modified amino acids, and/or may be interrupted by non-amino acids. The terms also encompass an amino acid chain that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It is understood that the polypeptides can occur as single chains or associated chains.

As known in the art, “polynucleotide,” or “nucleic acid,” as used interchangeably herein, refer to chains of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the chain. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports. The 5′ and 3′ terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2′-O-methyl-, 2′-O-allyl, 2′-fluoro- or 2′-azido-ribose, carbocyclic sugar analogs, alpha- or beta-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S(“thioate”), P(S)S (“dithioate”), (O)NR₂ (“amidate”), P(O)R, P(O)OR′, CO or CH₂ (“formacetal”), in which each R or R′ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (—O—) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

An antibody that “preferentially binds” or “specifically binds” (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances.

A “host cell” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this invention.

The term “compete”, as used herein with regard to an antibody, means that a first antibody, or an antigen-binding portion thereof, binds to an epitope in a manner sufficiently similar to the binding of a second antibody, or an antigen-binding portion thereof, such that the result of binding of the first antibody with its cognate epitope is detectably decreased in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. The alternative, where the binding of the second antibody to its epitope is also detectably decreased in the presence of the first antibody, can, but need not be the case. That is, a first antibody can inhibit the binding of a second antibody to its epitope without that second antibody inhibiting the binding of the first antibody to its respective epitope. However, where each antibody detectably inhibits the binding of the other antibody with its cognate epitope or ligand, whether to the same, greater, or lesser extent, the antibodies are said to “cross-compete” with each other for binding of their respective epitope(s). Both competing and cross-competing antibodies are encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or portion thereof), the skilled artisan would appreciate, based upon the teachings provided herein, that such competing and/or cross-competing antibodies are encompassed and can be useful for the methods disclosed herein.

As used herein, “treatment” is an approach for obtaining beneficial or desired clinical results.

As used herein, an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing incidence or amelioration of one or more symptoms of various diseases or conditions (such as, for example without limitation, renal cell, gastric, head and neck, lung, ovarian, and pancreatic cancers), decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication, and/or delaying the progression of the disease. An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

An “individual” or a “subject” is a mammal, more preferably, a human. Mammals also include, but are not limited to, farm animals, sport animals, pets, primates, horses, dogs, cats, mice and rats.

As used herein, “vector” means a construct, which is capable of delivering, and, preferably, expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

As used herein, “expression control sequence” means a nucleic acid sequence that directs transcription of a nucleic acid. An expression control sequence can be a promoter, such as a constitutive or an inducible promoter, or an enhancer. The expression control sequence is operably linked to the nucleic acid sequence to be transcribed.

The term “promoter” refers to a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence.

The term “promoter/regulatory sequence” refers to a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner.

The term “constitutive” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.

The term “inducible” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell.

The term “tissue-specific” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.

The term “flexible polypeptide linker” or “linker” as used in the context of a scFv refers to a peptide linker that consists of amino acids such as glycine and/or serine residues used alone or in combination, to link variable heavy and variable light chain regions together. In one embodiment, the flexible polypeptide linker is a Glycine/Serine linker and comprises the amino acid sequence (Gly-Gly-Gly-Ser)_(n) or (Gly-Gly-Gly-Gly-Ser)_(n), where n is a positive integer equal to or greater than 1. For example, n=1, n=2, n=3, n=4, n=5, n=6, n=7, n=8, n=9 and n=10. In one embodiment, the flexible polypeptide linkers include, but are not limited to, (Gly₄Ser)₄ or (Gly₄Ser)₃. In another embodiment, the linkers include multiple repeats of (Gly_(x)Ser)_(n), where x=1, 2, 3, 4 or 5 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, such as multiple repeat of (GlySer), (Gly₂Ser) or (Gly₅Ser). Also included within the scope of the invention are linkers described in WO2012/138475, incorporated herein by reference.

As used herein, a 5′ cap (also termed an RNA cap, an RNA 7-methylguanosine cap or an RNA m G cap) is a modified guanine nucleotide that has been added to the “front” or 5′ end of a eukaryotic messenger RNA shortly after the start of transcription. The 5′ cap consists of a terminal group which is linked to the first transcribed nucleotide. Its presence is critical for recognition by the ribosome and protection from RNases. Cap addition is coupled to transcription, and occurs co-transcriptionally, such that each influences the other. Shortly after the start of transcription, the 5′ end of the mRNA being synthesized is bound by a cap- synthesizing complex associated with RNA polymerase. This enzymatic complex catalyzes the chemical reactions that are required for mRNA capping. Synthesis proceeds as a multi- step biochemical reaction. The capping moiety can be modified to modulate functionality of mRNA such as its stability or efficiency of translation.

As used herein, “in vitro transcribed RNA” refers to RNA, preferably mRNA, that has been synthesized in vitro. Generally, the in vitro transcribed RNA is generated from an in vitro transcription vector. The in vitro transcription vector comprises a template that is used to generate the in vitro transcribed RNA.

As used herein, a “poly(A)” is a series of adenosines attached by polyadenylation to the mRNA. In the preferred embodiment of a construct for transient expression, the polyA is between 50 and 5000, preferably greater than 64, more preferably greater than 100, most preferably greater than 300 or 400. poly(A) sequences can be modified chemically or enzymatically to modulate mRNA functionality such as localization, stability or efficiency of translation.

As used herein, “polyadenylation” refers to the covalent linkage of a polyadenylyl moiety, or its modified variant, to a messenger RNA molecule. In eukaryotic organisms, most messenger RNA (mRNA) molecules are polyadenylated at the 3′ end. The 3′ poly(A) tail is a long sequence of adenine nucleotides (often several hundred) added to the pre-mRNA through the action of an enzyme, polyadenylate polymerase. In higher eukaryotes, the poly(A) tail is added onto transcripts that contain a specific sequence, the polyadenylation signal. The poly(A) tail and the protein bound to it aid in protecting mRNA from degradation by exonucleases. Polyadenylation is also important for transcription termination, export of the mRNA from the nucleus, and translation. Polyadenylation occurs in the nucleus immediately after transcription of DNA into RNA, but additionally can also occur later in the cytoplasm. After transcription has been terminated, the mRNA chain is cleaved through the action of an endonuclease complex associated with RNA polymerase. The cleavage site is usually characterized by the presence of the base sequence AAUAAA near the cleavage site. After the mRNA has been cleaved, adenosine residues are added to the free 3′ end at the cleavage site.

As used herein, “transient” refers to expression of a non-integrated transgene for a period of hours, days or weeks, wherein the period of time of expression is less than the period of time for expression of the gene if integrated into the genome or contained within a stable plasmid replicon in the host cell.

The term “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell. The phrase “cell surface receptor” includes molecules and complexes of molecules capable of receiving a signal and transmitting signal across the membrane of a cell.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.” Numeric ranges are inclusive of the numbers defining the range.

It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of” and/or “consisting essentially of” are also provided.

Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. The materials, methods, and examples are illustrative only and not intended to be limiting.

DESCRIPTION OF FIGURES

FIGS. 1 and 2 show the dual cell surface expression of P-CAR1 and various N-CARs assessed by multicolor flow cytometry in transduced NFAT-luciferase reporter Jurkat cells.

FIGS. 3 and 4 show the dual cell surface expression of P-CAR1 and various N-CARs assessed by multicolor flow cytometry in transduced NFkB-luciferase reporter Jurkat cells. In FIGS. 1 to 4, P-CAR expression was detected using a recombinant human CD19-mouse IgG Fc fusion protein followed by APC-conjugated F(ab′)2 goat anti-mouse Fcy (shown on x axis), and N-CAR expression was detected with a biotinylated recombinant human PSMA-human IgG1 Fc fusion protein followed by PE-conjugated streptavidin (y axis).

FIGS. 5A, 5B and 5C show the inhibitory effect of various N-CARs on P-CAR1 induced T cell activation. Control ΔPD1- or test N-CAR-transduced luciferase reporter Jurkat cells expressing P-CAR1 were incubated with either CD19-expressing AAPCs or dual CD19+PSMA-expressing AAPCs, and luciferase activity was assessed 16 h later. Data are expressed as a ratio of the mean RLU from co-culture with CD19+PSMA AAPCs/CD19 AAPCs. n=6 replicates per sample; data shown are the means+/− 95% Cl). FIGS. 5A/5C and 5B show results using NFAT-luciferase reporter and NFkB-luciferase reporter Jurkat cells, respectively.

FIGS. 6 and 7 show the dual cell surface expression of P-CAR2 and and N-CARs listed in Table 10 assessed by multicolor flow cytometry in transduced NFAT-luciferase reporter Jurkat cells. FIGS. 8 and 9 show the dual cell surface expression of P-CAR2 and N-CARs listed in Table 10 assessed by multicolor flow cytometry in transduced NFkB-luciferase reporter Jurkat cells. In FIGS. 6 to 9, P-CAR expression was detected using a recombinant human CD19-mouse IgG Fc fusion protein followed by APC-conjugated F(ab′)2 goat anti-mouse Fcy (shown on x axis), and N-CAR expression was detected with a biotinylated recombinant human PSMA-human IgG1 Fc fusion protein followed by PE-conjugated streptavidin (y axis).

FIGS. 10A and 10B show the inhibitory effect of various N-CARs on P-CAR2 induced T cell activation. Control ΔPD1- or test N-CAR-transduced luciferase reporter Jurkat cells expressing P-CAR2 were incubated with either CD19-expressing or dual PSMA/CD19-expressing AAPCs, and luciferase activity was assessed 16h later. Data are expressed as a ratio of the mean RLU from co-culture with CD19+PSMA AAPCs/CD19 AAPCs. n=6 replicates per sample; data shown are the means +/− 95%Cl. FIGS. 10A and 10B show results using NFAT-luciferase reporter and NFkB-luciferase reporter Jurkat cells, respectively.

DETAILED DESCRIPTION

The invention relates to a negative signal (or inhibitory) chimeric antigen receptor (N-CAR) comprising

an extracellular domain comprising an antigen binding domain,

a transmembrane domain, and,

an intracellular domain

wherein the intracellular domain comprises an immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TX₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I.

In some embodiments the term amino acid refers to a natural amino acid. In some embodiments, the term amino acid refer to an amino acid selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, cysteine, methionine, lysine, arginine, histidine, tryptophan, aspartic acid, glutamic acid, asparagine or glutamine.

In some embodiments, when the extracellular domain is a scFv against PSMA, then the intracellular domain is not the intracellular domain of human PD-1.

In some embodiments, the intracellular domain is not the intracellular domain of human PD-1.

In some embodiments, the intracellular domain is not the intracellular domain of human BTLA.

In some embodiments, the intracellular domain is not the intracellular domain of human CD244.

In some embodiments, the intracellular domain is not SEQ ID No 2000, SEQ ID No 2001 or SEQ ID No 2002.

In some embodiments, the extracellular domain does not bind to PMSA.

In some embodiments, the intracellular domain does not comprise the full intracellular domain of PD-1.

In some embodiments, the ITSM is not TEYATI.

The intracellular domain or region of the N-CAR includes an inhibitory intracellular signaling domain. An inhibitory intracellular signaling domain is generally responsible for inactivation of the signal from a positive intracellular signaling domain from a P-CAR on the same immune cell in which the N-CAR has been introduced, thereby blocking activation of a normal effector function of the immune cell. The term “effector function” refers to a specialized function of a cell. Effector function of a T-cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.

Intracellular Domain of the N-CAR

In some embodiments, the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0, 1 or an integer greater than 1;

m is 1 or an integer greater than 1;

p is 1 or an integer greater than 1;

L1 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (a) a naturally occurring N-terminal flanking region of an ITIM         only intracellular domain or a fragment thereof such as, for         example, any of the sequences shown in Table 3 below or a         fragment thereof;     -   (b) a naturally occurring N-terminal flanking region of an         ITIM.*ITSM intracellular domain or a fragment thereof, such as,         for example, any of the sequences shown in Table 1 below or a         fragment thereof;     -   (c) a naturally occurring intracellular domain from a known         inhibitory receptor such as any of the sequences shown in table         2 or a fragment thereof, wherein said intracellular domain is         N-terminally flanking to a sequence in (b) above; and     -   (d) a non-naturally occurring sequence comprising between 1 and         500 amino acids;

each of L2 and L3 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (e) a naturally occurring C-terminal flanking region of an ITIM         only intracellular domain, such as, for example, any of the         sequences shown in Table 4 below or a fragment thereof;     -   (f) a naturally occurring N-terminal flanking region of an ITSM         only intracellular domain such as, for example, any of the         sequences shown in Table 6 below or a fragment thereof;     -   (g) a naturally occurring intracellular domain between ITIM and         ITSM from proteins that have ITIM.*ITSM motif such as, for         example, any of the sequences shown in Table 5 below or a         fragment thereof;     -   (h) a naturally occurring intracellular domain from a known         inhibitory receptor such as any of the sequences shown in table         2 or a fragment thereof, wherein said intracellular domain is         N-terminally flanking to a sequence in (f) or (g) above; and     -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

L4 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (j) a naturally occurring C-terminal flanking region of an         ITIM.*ITSM intracellular domain or a fragment thereof such as,         for example, any of the sequences shown in Table 7 below or a         fragment thereof;     -   (k) a naturally occurring C-terminal flanking region of an ITSM         only intracellular domain such as, for example, any of the         sequences shown in Table 8 below or a fragment thereof;     -   (i) a naturally occurring intracellular domain from a known         inhibitory receptor such as any of the sequences shown in table         2 or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (j) or (k) above; and     -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids, and, wherein,

the ITIM is the sequence X₅X₆YX₇X₈X₉, wherein

X₅ is S, V, I or L,

X₆ is an amino acid,

X₇ is an amino acid,

X₈ is an amino acid, and,

X₉ is V, I or L, and,

the ITSM is the sequence TX₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I,

or a variant thereof.

In some embodiments, the known inhibitory receptor refers to an inhibitory receptor comprising an extracellular domain, a transmembrane domain and an intracellular domain which do not comprise any ITIM or ITSM and which provides a negative signal able to reduce the activation signal provided by the TCR/CD3 complex in a T-cell.

In some embodiments, the known inhibitory receptor refers to an inhibitory receptor comprising an extracellular domain, a transmembrane domain and an intracellular domain which provide a negative signal able to reduce the activation signal provided by the TCR/CD3 complex in a T-cell.

In some embodiments, the known inhibitory receptor is selected from CTLA4, LAG3 HAVCR2 (TIM3), KIR2DL2, LILRB1, TIGIT, CEACAM1, CSF1R, CDS, CD96, CD22 and LAIR1. In a preferred embodiment, the known inhibitory receptor is KIR2DL2.

ITIM.*ITSM intracellular domain refers to a domain comprising one ITIM and one ITSM.

ITSM only intracellular domain refers to a domain comprising one ITSM and no ITIM.

ITIM only intracellular domain refers to a domain comprising one ITIM and no ITSM.

When one or more of n, m or p are greater than 1, each occurrence of L1, L2, L3, L4, ITIM and ITSM is selected independently from the other. For example, the intracellular domain of the N-CAR may comprise several ITSM having different sequences.

In some embodiments, L1 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (a) a naturally occurring N-terminal flanking region of ITIM         only intracellular domains selected from

YKMYGSEMLHKRDPLDEDEDTD DHWALTQRTARAVSPQSTKPMAES CSRAARGTIGARRTGQPLKEDPSAVPVFS HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDRET DTSALAAGSSQE KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEE LTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCG EQRGEDCAELHDYFNV KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSD RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPG WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKED KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTY

-   -   (b) a naturally occurring N-terminal flanking region of         ITIM.*ITSM intracellular domains selected from

YKMYGSEMLHKRDPLDEDEDTD WRMMKYQQKAAGMSPEQVLQPLEGD CSRAARGTIGARRTGQPLKEDPSAVPVFS RIRQKKAQGSTSSTRLHEPEKNAREITQDTND KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEE KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSD RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPG KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTY

-   -   (c) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table         2, wherein said intracellular domain is N- terminally flanking         to a sequence in (b) above; and     -   (d) a non-naturally occurring sequence comprising between 1 and         500 amino acids.

In some embodiments, each of L2 and L3 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (e) a naturally occurring C-terminal flanking region of ITIM         only intracellular domains selected from;

GNCSFFTETG NFHGMNPSKDTSTEYSEVRTQ KEEEMADTSYGTVKAENIIMMETAQTSL NHSVIGPNSRLARNVKEAPTEYASICVRS DHWALTQRTARAVSPQSTKPMAESITYAAVARH QVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT DFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQP LRPEDGHCSWPL NLPKGKKPAPQAAEPNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRTP KQPAPKPEPSFSEYASVQVPRK TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED QEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTVC VADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAFGV TMWEIATRGMTPYPGVQNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWR TDPLDRPTFSVLRLQLEKLLESLPDVRNQADVIYVNTQLLESSEGLAQGS TLAPLDLNIDPDSIIASCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEW EDLTSAPSAAVTAEKNSVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFA DDSSEGSEVLM

-   -   (f) a naturally occurring N-terminal flanking region of ITSM         only intracellular domains selected from;

YKMYGSEMLHKRDPLDEDEDTDISYKKLKEEEMAD CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA AEPNNH KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEELHYASLNFHGMNPSKDTS KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEA P WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI QSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPP ASARSSVGEGELQYASLSFQMVKPWDSRGQEATD NKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQGH IIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKM LVAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVF EYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMV YLAGLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYS KLARHSKFGMKGPASVISNDDDSASPLHHISNGSNTPSSSEGGPDAVIIG MTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFL AECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFY GVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQML HIAQQIAAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYS KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSA KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTYLLYSRLETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAA RNCMLRDDMTVCVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRV YTSKSDVWAFGVTMWEIATRGM

-   -   (g) a naturally occurring intracellular domain between ITIM and         ITSM from proteins that have ITIM.*ITSM motif selected from;

KEEEMAD NFHGMNPSKDTS QVSSAESHKDLGKKDTE NLPKGKKPAPQAAEPNNH NHSVIGPNSRLARNVKEAP DFQWREKTPEPPVPCVPEQ TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED QEPTYCNMGHLSSHLPGRGPEEP ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTVC VADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAFGV TMWEIATRGM

-   -   (h) a naturally occurring intracellular domain from known         inhibitory receptors selected from the sequences shown in table         2 wherein said intracellular domain is N-terminally flanking to         a sequence in (f) or (g) above; and     -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids.

In some embodiments, L4 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (j) a naturally occurring C-terminal flanking region of         ITIM.*ITSM intracellular domains selected from:

SRP RTQ CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM

-   -   (k) a naturally occurring C-terminal flanking region of ITSM         only intracellular domain selected from

RTQ SRP KIHR CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT RKPQVVPPPQQNDLEIPESPTYENFT GKSQPKAQNPARLSRKELENFDVYS VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK FNLQGKTPVSQKEESSATIYCSIRKPQVVPPPQQNDLEIPESPTYENFT GGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSN TEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQA LAQAPPVYLDVLG GGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSN NEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTLLQN LAKASPVYLDILG QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM KDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSR KSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS

-   -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table 2         wherein said intracellular domain is C-terminally flanking to a         sequence in (j) or (k) above; and     -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids.

In some embodiments the intracellular domain comprises the sequence (L3-ITSM-L4)^(m) (i.e, n is 0 and p is 1).

In some embodiments, the intracellular domain comprises the sequence L3-ITSM-L4 (i.e, n is 0, m is 1 and p is 1).

In some embodiments, the intracellular domain comprises the sequence L3-ITSM-L4-L3- ITSM-L4 (i.e, n is 0, m is 2 and p is 1).

In some embodiments, the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1;

L3 comprises one sequence selected from

-   -   (f) a naturally occurring N-terminal flanking region of an ITSM         only intracellular domain such as, for example, any of the         sequences shown in Table 6 below or a fragment thereof; or,     -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

L4 comprises one or more, preferably one or two, sequences selected from the group consisting of:

-   -   (k) a naturally occurring C-terminal flanking region of an ITSM         only intracellular domain such as, for example, any of the         sequences shown in Table 8 below or a fragment thereof;     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor such as any of the sequences shown in table         2 or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above; and     -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids, and, wherein,

the ITSM is the sequence TX₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I,

or a variant thereof.

In some embodiments, the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

YKMYGSEMLHKRDPLDEDEDTDISYKKLKEEEMAD CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA AEPNNH KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEELHYASLNFHGMNPSKDTS KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEA P WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI SQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPP ASARSSVGEGELQYASLSFQMVKPWDSRGQEATD NKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQGH IIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKM LVAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVF EYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMV YLAGLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYS KLARHSKFGMKGPASVISNDDDSASPLHHISNGSNTPSSSEGGPDAVIIG MTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFL AECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFY GVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQML HIAQQIAAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYS KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSA KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTYLLYSRLETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAA RNCMLRDDMTVCVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRV YTSKSDVWAFGVTMWEIATRGM and L4 comprises one sequence selected from the group consisting of (k)

RTQ SRP KIHR CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT RKPQVVPPPQQNDLEIPESPTYENFT GKSQPKAQNPARLSRKELENFDVYS VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK FNLQGKTPVSQKEESSATIYCSIRKPQVVPPPQQNDLEIPESPTYENFT GGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSN EAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQAL AQAPPVYLDVLG GGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSN NEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTLLQN LAKASPVYLDILG QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM KDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSR KSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS

-   -   and optionally     -   (I) a naturally occurring intracellular domain from a known         inhibitory receptor such as any of the sequences shown in table         2 or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above;

and the ITSM is the sequence TX₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I,

or a variant thereof.

In some embodiments, the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA AEPNNH KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEA P WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI QSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPP SARSSVGEGELQYASLSFQMVKPWDSRGQEATD KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSA

L4 comprises one sequence selected from the group consisting of (k)

SRP KIHR CVRS RKAVPDAVESRYSRTEGSLDGT RKPQVVPPPQQNDLEIPESPTYENFT GKSQPKAQNPARLSRKELENFDVYS VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK

-   -   and optionally     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table 2         or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above;

and the ITSM is the sequence TX₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I,

or a variant thereof.

In some embodiments, the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ and L4 comprises

(k)

VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL

-   -   and     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table 2         or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above;         and the ITSM is the sequence TX₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I,

or a variant thereof.

In some embodiments, the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP

L4 comprises

(k)

SRP

-   -   and optionally     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table 2         or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above;

and the ITSM is the sequence TX₁₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I,

or a variant thereof.

In some embodiments, the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1 or 2;

L3 comprises one sequence selected from

-   -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

L4 comprises one or more, preferably one or two, sequences selected from:

-   -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids, and, wherein,

the ITSM is the sequence TX₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I.

In some embodiments, the intracellular domain comprises the sequence (L1-ITIM-L2-L3-ITSM-L4)^(p) wherein

p is 1, 2, 3, 4 or 5;

L1 is a naturally occurring N-terminal flanking region of an ITIM only intracellular domain or a fragment thereof such as, for example, any of the sequences shown in Table 3 below or a fragment thereof;

L2 is absent;

L3 is a naturally occurring intracellular domain between ITIM and ITSM from proteins that have ITIM.*ITSM motif or a fragment thereof such as, for example, any of the sequences shown in Table 5 below or a fragment thereof;

L4 is a naturally occurring C-terminal flanking region of an ITIM.*ITSM intracellular domain or a fragment thereof such as, for example, any of the sequences shown in Table 7 below or a fragment thereof; or a naturally occurring C-terminal flanking region of ITSM only intracellular domain or a fragment thereof such as, for example, any of the sequences shown in Table 8 below or a fragment thereof.

In some embodiments, the intracellular domain comprises the sequence (L1-ITIM-L2-L3-ITSM-L4)^(p) wherein

p is 1, 2, 3, 4 or 5;

L1 is a naturally occurring N-terminal flanking region of ITIM only intracellular domains selected from the following sequences;

YKMYGSEMLHKRDPLDEDEDTD DHWALTQRTARAVSPQSTKPMAES CSRAARGTIGARRTGQPLKEDPSAVPVFS HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDRET DTSALAAGSSQE KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEE LTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCG EQRGEDCAELHDYFNV KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSD RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPG WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKED KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTY

L2 is absent;

L3 is a naturally occurring intracellular domain between ITIM and ITSM from proteins that have ITIM.*ITSM motif selected from the following sequences:

KEEEMAD NFHGMNPSKDTS QVSSAESHKDLGKKDTE NLPKGKKPAPQAAEPNNH NHSVIGPNSRLARNVKEAP DFQWREKTPEPPVPCVPEQ TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED QEPTYCNMGHLSSHLPGRGPEEP ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTVC VADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAFGV TMWEIATRGM

L4 is a naturally occurring C-terminal flanking region of ITIM.*ITSM intracellular domains selected from the following sequences:

SRP RTQ CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM

-   -   or a naturally occurring C-terminal flanking region of ITSM only         intracellular domains selected from the following sequences:

RTQ SRP CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK FNLQGKTPVSQKEESSATIYCSIRKPQVVPPPQQNDLEIPESPTYENFT GGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSN TEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQA LAQAPPVYLDVLG GGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSN NEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTLLQN LAKASPVYLDILG QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM KDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSR KSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS. or a variant thereof.

In some embodiments, the non-naturally occurring sequence of (d), (i) and (m) comprises between 1 and 500 amino acids, preferably 1 to 400, 1 to 300, 1 to 200, 1 to 100, 10 to 100, 10 to 80, 10 to 60, 10 to 40, 100 to 200, 100 to 300 or 100 to 400.

In some embodiments, the non-naturally occurring sequence of (d) or (i) is a Glycine/Serine linker (Gly_(x)Ser)_(n) where x=1, 2, 3, 4 or 5 and n is 1 to 100. Preferably the Glycine/Serine linker comprises the amino acid sequence (Gly-Gly-Gly-Ser)_(n) or (Gly-Gly-Gly-Gly-Ser)_(n), where n is a positive integer equal to or greater than 1, preferably between 1 to 100, 1 to 80, 1 to 50, 1 to 20 or 1 to 10. For example, n=1, n=2, n=3, n=4, n=5, n=6, n=7, n=8, n=9 and n=10. In one embodiment, the glycine/serine linkers include, but are not limited to, (Gly₄Ser)₄ or (Gly₄Ser)₃.

In some embodiments, X₁ is E, V or I.

In some embodiments, X₁ is E.

In some embodiments, X₂ is S or A.

In some embodiments, X₂ is A.

In some embodiments, X₃ is E, S, T, Q or V.

In some embodiments, X₃ is E.

In some embodiments, X₃ is T.

In some embodiments, X₂ is I.

In some embodiments, X₅ is L, V or I.

In some embodiments, X₅ is L.

In some embodiments, X₅ is V.

In some embodiments, X₅ is I.

In some embodiments, X₆ is A, H, Q, T, D, V, L or E.

In some embodiments, X₆ is H.

In some embodiments, X₆ is D.

In some embodiments, X₇ is A, G, T, V or E.

In some embodiments, X₇ is A.

In some embodiments, X₇ is G.

In some embodiments, X₈ is V, S, D or E.

In some embodiments, X₈ is S or E.

In some embodiments, X₈ is E.

In some embodiments, X₉ is L or V.

In some embodiments, X₉ is L.

In some embodiments, X₅ is L or V, X₈ is E and X₉ is L.

In some embodiments, the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain, is selected from SEQ ID No 926 to SEQ ID No 1015 (see below table).

TAYELV SEQ ID No 926 TAYGLI SEQ ID No 927 TAYNAV SEQ ID No 928 TCYGLV SEQ ID No 929 TCYPDI SEQ ID No 930 TDYASI SEQ ID No 931 TDYDLV SEQ ID No 932 TDYLSI SEQ ID No 933 TDYQQV SEQ ID No 934 TDYYRV SEQ ID No 935 TEYASI SEQ ID No 936 TEYATI SEQ ID No 937 TEYDTI SEQ ID No 938 TEYPLV SEQ ID No 939 TEYSEI SEQ ID No 940 TEYSEV SEQ ID No 941 TEYSTI SEQ ID No 942 TEYTKV SEQ ID No 943 TFYHVV SEQ ID No 944 TFYLLI SEQ ID No 945 TFYNKI SEQ ID No 946 TFYPDI SEQ ID No 947 TGYEDV SEQ ID No 948 TGYLSI SEQ ID No 949 THYKEI SEQ ID No 950 TIYAQV SEQ ID No 951 TIYAVV SEQ ID No 952 TIYCSI SEQ ID No 953 TIYEDV SEQ ID No 954 TIYERI SEQ ID No 955 TAYELV SEQ ID No 86 TIYEVI SEQ ID No 956 TIYHVI SEQ ID No 957 TIYIGV SEQ ID No 958 TIYLKV SEQ ID No 959 TIYSMI SEQ ID No 960 TIYSTI SEQ ID No 961 TIYTYI SEQ ID No 962 TKYFHI SEQ ID No 963 TKYMEI SEQ ID No 964 TKYQSV SEQ ID No 965 TKYSNI SEQ ID No 966 TKYSTV SEQ ID No 967 TLYASV SEQ ID No 968 TLYAVV SEQ ID No 969 TLYFWV SEQ ID No 970 TLYHLV SEQ ID No 971 TLYPMV SEQ ID No 972 TLYPPI SEQ ID No 973 TLYRDI SEQ ID No 974 TLYRDV SEQ ID No 975 TLYSKI SEQ ID No 976 TLYSLI SEQ ID No 977 TLYSPV SEQ ID No 978 TMYAQV SEQ ID No 979 TMYCQV SEQ ID No 980 TNYKAV SEQ ID No 981 TNYNLV SEQ ID No 982 TPYAGI SEQ ID No 983 TPYPGV SEQ ID No 984 TPYVDI SEQ ID No 985 TAYELV SEQ ID No 86 TQYGRV SEQ ID No 986 TQYNQV SEQ ID No 987 TRYAYV SEQ ID No 988 TRYGEV SEQ ID No 989 TRYHSV SEQ ID No 990 TRYKTI SEQ ID No 991 TRYLAI SEQ ID No 992 TRYMAI SEQ ID No 993 TRYQKI SEQ ID No 994 TRYQQI SEQ ID No 995 TRYSNI SEQ ID No 996 TRYSPI SEQ ID No 997 TSYGTV SEQ ID No 998 TSYMEV SEQ ID No 999 TSYQGV SEQ ID No 1000 TSYTTI SEQ ID No 1001 TTYRSI SEQ ID No 1002 TTYSDV SEQ ID No 1003 TTYVTI SEQ ID No 1004 TVYAQI SEQ ID No 1005 TVYASV SEQ ID No 1006 TVYEVI SEQ ID No 1007 TVYGDV SEQ ID No 1008 TVYKGI SEQ ID No 1009 TVYQRV SEQ ID No 1010 TVYSEV SEQ ID No 1011 TVYSTV SEQ ID No 1012 TYYHSI SEQ ID No 1013 TYYLQI SEQ ID No 1014 TYYYSV SEQ ID No 1015 TAYELV SEQ ID No 86

In some embodiments, the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TEYASI.

In some embodiments, the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TEYSEI.

In some embodiments, the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TVYSEV.

In some embodiments, the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TEYSTI.

In some embodiments, the ITIM, or at least one of the ITIMs when several ITIMs are present in the intracellular domain is selected from SEQ ID No 1016 to SEQ ID 1998 (see below table).

LLYEMV SEQ ID No 1016 ITYFAL SEQ ID No 1017 ISYKGL SEQ ID No 1018 LAYHTV SEQ ID No 1019 VQYLRL SEQ ID No 1020 LTYVLL SEQ ID No 1021 VRYSIV SEQ ID No 1022 LLYLLL SEQ ID No 1023 IAYGDI SEQ ID No 1024 IAYRDL SEQ ID No 1025 IAYSLL SEQ ID No 1026 IAYSRL SEQ ID No 1027 ICYALL SEQ ID No 1028 ICYDAL SEQ ID No 1029 ICYPLL SEQ ID No 1030 ICYQLI SEQ ID No 1031 IDYILV SEQ ID No 1032 IDYKTL SEQ ID No 1033 IDYTQL SEQ ID No 1034 IDYYNL SEQ ID No 1035 IEYCKL SEQ ID No 1036 IEYDQI SEQ ID No 1037 IEYGPL SEQ ID No 1038 IEYIRV SEQ ID No 1039 IEYKSL SEQ ID No 1040 IEYKTL SEQ ID No 1041 IEYSVL SEQ ID No 1042 IEYWGI SEQ ID No 1043 IFYGNV SEQ ID No 1044 IFYHNL SEQ ID No 1045 IFYKDI SEQ ID No 1046 IFYQNV SEQ ID No 1047 IFYRLI SEQ ID No 1048 IGYDIL SEQ ID No 1049 IGYDVL SEQ ID No 1050 IGYICL SEQ ID No 1051 IGYKAI SEQ ID No 1052 IGYLEL SEQ ID No 1053 IGYLPL SEQ ID No 1054 IGYLRL SEQ ID No 1055 IGYPFL SEQ ID No 1056 IGYSDL SEQ ID No 1057 IHYRQI SEQ ID No 1058 IHYSEL SEQ ID No 1059 IIYAFL SEQ ID No 1060 IIYHVI SEQ ID No 1061 IIYMFL SEQ ID No 1062 IIYNLL SEQ ID No 1063 IIYNNL SEQ ID No 1064 IIYSEV SEQ ID No 1065 IKYCLV SEQ ID No 1066 IKYKEL SEQ ID No 1067 IKYLAL SEQ ID No 1068 IKYTCI SEQ ID No 1069 ILYADI SEQ ID No 1070 ILYAFL SEQ ID No 1071 ILYCSV SEQ ID No 1072 ILYEGL SEQ ID No 1073 ILYELL SEQ ID No 1074 ILYFQI SEQ ID No 1075 ILYHTV SEQ ID No 1076 ILYLQV SEQ ID No 1077 ILYSIL SEQ ID No 1078 ILYSVL SEQ ID No 1079 ILYTEL SEQ ID No 1080 ILYTIL SEQ ID No 1081 IMYTLV SEQ ID No 1082 INYCSV SEQ ID No 1083 INYKDI SEQ ID No 1084 INYTTV SEQ ID No 1085 INYVLL SEQ ID No 1086 IPYDVL SEQ ID No 1087 IPYLLV SEQ ID No 1088 IPYRTV SEQ ID No 1089 IPYSQL SEQ ID No 1090 IPYSRI SEQ ID No 1091 IPYTQI SEQ ID No 1092 IQYAPL SEQ ID No 1093 IQYASL SEQ ID No 1094 IQYERL SEQ ID No 1095 IQYGII SEQ ID No 1096 IQYGNV SEQ ID No 1097 IQYGRV SEQ ID No 1098 IQYNVV SEQ ID No 1099 IQYRSI SEQ ID No 1100 IQYTEL SEQ ID No 1101 IQYWGI SEQ ID No 1102 IRYANL SEQ ID No 1103 IRYLDL SEQ ID No 1104 IRYPLL SEQ ID No 1105 IRYRLL SEQ ID No 1106 IRYRTI SEQ ID No 1107 ISYASL SEQ ID No 1108 ISYCGV SEQ ID No 1109 ISYEPI SEQ ID No 1110 ISYFQI SEQ ID No 1111 ISYGLI SEQ ID No 1112 ISYKKL SEQ ID No 1113 ISYLPL SEQ ID No 1114 ISYPML SEQ ID No 1115 ISYTTL SEQ ID No 1116 ITYAAV SEQ ID No 1117 ITYADL SEQ ID No 1118 ITYAEL SEQ ID No 1119 ITYAEV SEQ ID No 1120 ITYASV SEQ ID No 1121 ITYDLI SEQ ID No 1122 ITYENV SEQ ID No 1123 ITYQLL SEQ ID No 1124 ITYSLL SEQ ID No 1125 IVYAEL SEQ ID No 1126 IVYALV SEQ ID No 1127 IVYASL SEQ ID No 1128 IVYEIL SEQ ID No 1129 IVYFIL SEQ ID No 1130 IVYHML SEQ ID No 1131 IVYLCI SEQ ID No 1132 IVYRLL SEQ ID No 1133 IVYSAL SEQ ID No 1134 IVYSWV SEQ ID No 1135 IVYTEL SEQ ID No 1136 IVYYIL SEQ ID No 1137 IWYENL SEQ ID No 1138 IWYFVV SEQ ID No 1139 IWYNIL SEQ ID No 1140 IYYLGV SEQ ID No 1141 LAYALL SEQ ID No 1142 LAYARI SEQ ID No 1143 LAYDSV SEQ ID No 1144 LAYFGV SEQ ID No 1145 LAYHRL SEQ ID No 1146 LAYKDL SEQ ID No 1147 LAYKRI SEQ ID No 1148 LAYPPL SEQ ID No 1149 LAYQTL SEQ ID No 1150 LAYREV SEQ ID No 1151 LAYRII SEQ ID No 1152 LAYRLL SEQ ID No 1153 LAYSQL SEQ ID No 1154 LAYSSV SEQ ID No 1155 LAYTLL SEQ ID No 1156 LAYWGI SEQ ID No 1157 LAYYTV SEQ ID No 1158 LCYADL SEQ ID No 1159 LCYAIL SEQ ID No 1160 LCYFHL SEQ ID No 1161 LCYHPI SEQ ID No 1162 LCYKEI SEQ ID No 1163 LCYKFL SEQ ID No 1164 LCYMII SEQ ID No 1165 LCYRKI SEQ ID No 1166 LCYRVL SEQ ID No 1167 LCYSTV SEQ ID No 1168 LCYTLV SEQ ID No 1169 LDYASI SEQ ID No 1170 LDYCEL SEQ ID No 1171 LDYDKI SEQ ID No 1172 LDYDKL SEQ ID No 1173 LDYDYL SEQ ID No 1174 LDYDYV SEQ ID No 1175 LDYEFL SEQ ID No 1176 LDYINV SEQ ID No 1177 LDYNNL SEQ ID No 1178 LDYPHV SEQ ID No 1179 LDYSPV SEQ ID No 1180 LDYVEI SEQ ID No 1181 LDYWGI SEQ ID No 1182 LEYAPV SEQ ID No 1183 LEYIPL SEQ ID No 1184 LEYKTI SEQ ID No 1185 LEYLCL SEQ ID No 1186 LEYLKL SEQ ID No 1187 LEYLQI SEQ ID No 1188 LEYLQL SEQ ID No 1189 LEYQRL SEQ ID No 1190 LEYVDL SEQ ID No 1191 LEYVSV SEQ ID No 1192 LEYYQI SEQ ID No 1193 LFYAQL SEQ ID No 1194 LFYCSV SEQ ID No 1195 LFYERV SEQ ID No 1196 LFYGFL SEQ ID No 1197 LFYKYV SEQ ID No 1198 LFYLLL SEQ ID No 1199 LFYNKV SEQ ID No 1200 LFYRHL SEQ ID No 1201 LFYTLL SEQ ID No 1202 LFYWDV SEQ ID No 1203 LFYWKL SEQ ID No 1204 LGYGNV SEQ ID No 1205 LGYKEL SEQ ID No 1206 LGYLQL SEQ ID No 1207 LGYPLI SEQ ID No 1208 LGYPWV SEQ ID No 1209 LGYSAL SEQ ID No 1210 LGYSDL SEQ ID No 1211 LGYVTL SEQ ID No 1212 LHYAKI SEQ ID No 1213 LHYALV SEQ ID No 1214 LHYANL SEQ ID No 1215 LHYARL SEQ ID No 1216 LHYASI SEQ ID No 1217 LHYASL SEQ ID No 1218 LHYASV SEQ ID No 1219 LHYATI SEQ ID No 1220 LHYATL SEQ ID No 1221 LHYAVL SEQ ID No 1222 LHYDVV SEQ ID No 1223 LHYEGL SEQ ID No 1224 LHYETI SEQ ID No 1225 LHYFEI SEQ ID No 1226 LHYFVV SEQ ID No 1227 LHYGAI SEQ ID No 1228 LHYILI SEQ ID No 1229 LHYINL SEQ ID No 1230 LHYKRI SEQ ID No 1231 LHYLDL SEQ ID No 1232 LHYLNI SEQ ID No 1233 LHYLTI SEQ ID No 1234 LHYLVI SEQ ID No 1235 LHYMAI SEQ ID No 1236 LHYMII SEQ ID No 1237 LHYMNI SEQ ID No 1238 LHYMTI SEQ ID No 1239 LHYMTL SEQ ID No 1240 LHYMTV SEQ ID No 1241 LHYMVI SEQ ID No 1242 LHYNML SEQ ID No 1243 LHYPAL SEQ ID No 1244 LHYPDL SEQ ID No 1245 LHYPII SEQ ID No 1246 LHYPIL SEQ ID No 1247 LHYPLL SEQ ID No 1248 LHYPML SEQ ID No 1249 LHYPNV SEQ ID No 1250 LHYPSI SEQ ID No 1251 LHYPTI SEQ ID No 1252 LHYPTL SEQ ID No 1253 LHYPTV SEQ ID No 1254 LHYPVI SEQ ID No 1255 LHYPVL SEQ ID No 1256 LHYRII SEQ ID No 1257 LHYRTI SEQ ID No 1258 LHYSII SEQ ID No 1259 LHYSSI SEQ ID No 1260 LHYSTI SEQ ID No 1261 LHYSTL SEQ ID No 1262 LHYSVI SEQ ID No 1263 LHYTAI SEQ ID No 1264 LHYTAL SEQ ID No 1265 LHYTII SEQ ID No 1266 LHYTKV SEQ ID No 1267 LHYTLI SEQ ID No 1268 LHYTSI SEQ ID No 1269 LHYTTI SEQ ID No 1270 LHYTTV SEQ ID No 1271 LHYTVI SEQ ID No 1272 LHYTVL SEQ ID No 1273 LHYTVV SEQ ID No 1274 LHYVSI SEQ ID No 1275 LHYVTI SEQ ID No 1276 LHYVVI SEQ ID No 1277 LIYEKL SEQ ID No 1278 LIYENV SEQ ID No 1279 LIYKDL SEQ ID No 1280 LIYNSL SEQ ID No 1281 LIYSGL SEQ ID No 1282 LIYTLL SEQ ID No 1283 LIYTVL SEQ ID No 1284 LIYWEI SEQ ID No 1285 LKYCEL SEQ ID No 1286 LKYDKL SEQ ID No 1287 LKYESL SEQ ID No 1288 LKYFTI SEQ ID No 1289 LKYHTV SEQ ID No 1290 LKYILL SEQ ID No 1291 LKYIPI SEQ ID No 1292 LKYKHV SEQ ID No 1293 LKYLYL SEQ ID No 1294 LKYMEV SEQ ID No 1295 LKYMTL SEQ ID No 1296 LKYPAI SEQ ID No 1297 LKYPDV SEQ ID No 1298 LKYPEL SEQ ID No 1299 LKYQPI SEQ ID No 1300 LKYRGL SEQ ID No 1301 LKYRLL SEQ ID No 1302 LLYADL SEQ ID No 1303 LLYAPL SEQ ID No 1304 LLYAVV SEQ ID No 1305 LLYCAI SEQ ID No 1306 LLYEHV SEQ ID No 1307 LLYELL SEQ ID No 1308 LLYEQL SEQ ID No 1309 LLYGQI SEQ ID No 1310 LLYIRL SEQ ID No 1311 LLYKAL SEQ ID No 1312 LLYKFL SEQ ID No 1313 LLYKLL SEQ ID No 1314 LLYKTV SEQ ID No 1315 LLYMVV SEQ ID No 1316 LLYNAI SEQ ID No 1317 LLYNIV SEQ ID No 1318 LLYNVI SEQ ID No 1319 LLYPAI SEQ ID No 1320 LLYPLI SEQ ID No 1321 LLYPNI SEQ ID No 1322 LLYPSL SEQ ID No 1323 LLYPTI SEQ ID No 1324 LLYPVI SEQ ID No 1325 LLYPVV SEQ ID No 1326 LLYQIL SEQ ID No 1327 LLYQNI SEQ ID No 1328 LLYRLL SEQ ID No 1329 LLYRVI SEQ ID No 1330 LLYSII SEQ ID No 1331 LLYSLI SEQ ID No 1332 LLYSPV SEQ ID No 1333 LLYSRL SEQ ID No 1334 LLYSTI SEQ ID No 1335 LLYSVI SEQ ID No 1336 LLYSVV SEQ ID No 1337 LLYTTI SEQ ID No 1338 LLYTVI SEQ ID No 1339 LLYTVV SEQ ID No 1340 LLYVII SEQ ID No 1341 LLYVIL SEQ ID No 1342 LLYVTI SEQ ID No 1343 LLYWGI SEQ ID No 1344 LLYYLL SEQ ID No 1345 LLYYVI SEQ ID No 1346 LMYDNV SEQ ID No 1347 LMYMVV SEQ ID No 1348 LMYQEL SEQ ID No 1349 LMYRGI SEQ ID No 1350 LNYACL SEQ ID No 1351 LNYATI SEQ ID No 1352 LNYEVI SEQ ID No 1353 LNYGDL SEQ ID No 1354 LNYHKL SEQ ID No 1355 LNYMVL SEQ ID No 1356 LNYNIV SEQ ID No 1357 LNYPVI SEQ ID No 1358 LNYQMI SEQ ID No 1359 LNYSGV SEQ ID No 1360 LNYSVI SEQ ID No 1361 LNYTIL SEQ ID No 1362 LNYTTI SEQ ID No 1363 LNYVPI SEQ ID No 1364 LPYADL SEQ ID No 1365 LPYALL SEQ ID No 1366 LPYFNI SEQ ID No 1367 LPYFNV SEQ ID No 1368 LPYHDL SEQ ID No 1369 LPYKLI SEQ ID No 1370 LPYKTL SEQ ID No 1371 LPYLGV SEQ ID No 1372 LPYLKV SEQ ID No 1373 LPYPAL SEQ ID No 1374 LPYQVV SEQ ID No 1375 LPYRTV SEQ ID No 1376 LPYVEI SEQ ID No 1377 LPYYDL SEQ ID No 1378 LQYASL SEQ ID No 1379 LQYERI SEQ ID No 1380 LQYFAV SEQ ID No 1381 LQYFSI SEQ ID No 1382 LQYHNI SEQ ID No 1383 LQYIGL SEQ ID No 1384 LQYIKI SEQ ID No 1385 LQYLSL SEQ ID No 1386 LQYMIV SEQ ID No 1387 LQYPAI SEQ ID No 1388 LQYPLL SEQ ID No 1389 LQYPLV SEQ ID No 1390 LQYPSI SEQ ID No 1391 LQYPTL SEQ ID No 1392 LQYPVL SEQ ID No 1393 LQYRAV SEQ ID No 1394 LQYSAI SEQ ID No 1395 LQYSSI SEQ ID No 1396 LQYSVI SEQ ID No 1397 LQYTIL SEQ ID No 1398 LQYTLI SEQ ID No 1399 LQYTMI SEQ ID No 1400 LQYYQV SEQ ID No 1401 LRYAAV SEQ ID No 1402 LRYAGL SEQ ID No 1403 LRYAPL SEQ ID No 1404 LRYASI SEQ ID No 1405 LRYATI SEQ ID No 1406 LRYATV SEQ ID No 1407 LRYAVL SEQ ID No 1408 LRYCGI SEQ ID No 1409 LRYELL SEQ ID No 1410 LRYETL SEQ ID No 1411 LRYGAL SEQ ID No 1412 LRYGPI SEQ ID No 1413 LRYGTL SEQ ID No 1414 LRYHHI SEQ ID No 1415 LRYHSI SEQ ID No 1416 LRYHVL SEQ ID No 1417 LRYIAI SEQ ID No 1418 LRYIFV SEQ ID No 1419 LRYITV SEQ ID No 1420 LRYKEV SEQ ID No 1421 LRYKKL SEQ ID No 1422 LRYKMV SEQ ID No 1423 LRYKSL SEQ ID No 1424 LRYKVI SEQ ID No 1425 LRYLAI SEQ ID No 1426 LRYLDL SEQ ID No 1427 LRYLTI SEQ ID No 1428 LRYLTV SEQ ID No 1429 LRYMSI SEQ ID No 1430 LRYMVI SEQ ID No 1431 LRYNCI SEQ ID No 1432 LRYNGL SEQ ID No 1433 LRYNII SEQ ID No 1434 LRYNIL SEQ ID No 1435 LRYNKI SEQ ID No 1436 LRYNSL SEQ ID No 1437 LRYNVI SEQ ID No 1438 LRYNVL SEQ ID No 1439 LRYPFL SEQ ID No 1440 LRYPII SEQ ID No 1441 LRYPIL SEQ ID No 1442 LRYPLL SEQ ID No 1443 LRYPNI SEQ ID No 1444 LRYPSI SEQ ID No 1445 LRYPTI SEQ ID No 1446 LRYPTL SEQ ID No 1447 LRYPVI SEQ ID No 1448 LRYPVL SEQ ID No 1449 LRYQKL SEQ ID No 1450 LRYQMI SEQ ID No 1451 LRYQNL SEQ ID No 1452 LRYRLI SEQ ID No 1453 LRYRVI SEQ ID No 1454 LRYSAI SEQ ID No 1455 LRYSDL SEQ ID No 1456 LRYSII SEQ ID No 1457 LRYSMI SEQ ID No 1458 LRYSSI SEQ ID No 1459 LRYSTI SEQ ID No 1460 LRYSTL SEQ ID No 1461 LRYSVI SEQ ID No 1462 LRYSVL SEQ ID No 1463 LRYSVV SEQ ID No 1464 LRYTAI SEQ ID No 1465 LRYTIL SEQ ID No 1466 LRYTLI SEQ ID No 1467 LRYTMI SEQ ID No 1468 LRYTNL SEQ ID No 1469 LRYTPV SEQ ID No 1470 LRYTSI SEQ ID No 1471 LRYTSV SEQ ID No 1472 LRYTTI SEQ ID No 1473 LRYTTV SEQ ID No 1474 LRYTVI SEQ ID No 1475 LRYVEV SEQ ID No 1476 LRYVTI SEQ ID No 1477 LRYVTV SEQ ID No 1478 LSYDSL SEQ ID No 1479 LSYEDV SEQ ID No 1480 LSYFGV SEQ ID No 1481 LSYILI SEQ ID No 1482 LSYISV SEQ ID No 1483 LSYKQV SEQ ID No 1484 LSYKRL SEQ ID No 1485 LSYLDV SEQ ID No 1486 LSYMDL SEQ ID No 1487 LSYNAL SEQ ID No 1488 LSYNDL SEQ ID No 1489 LSYNKL SEQ ID No 1490 LSYNQL SEQ ID No 1491 LSYPVL SEQ ID No 1492 LSYQEV SEQ ID No 1493 LSYQPV SEQ ID No 1494 LSYQTI SEQ ID No 1495 LSYRSL SEQ ID No 1496 LSYRSV SEQ ID No 1497 LSYSII SEQ ID No 1498 LSYSSL SEQ ID No 1499 LSYSTL SEQ ID No 1500 LSYTKV SEQ ID No 1501 LSYTSI SEQ ID No 1502 LSYTTI SEQ ID No 1503 LSYVLI SEQ ID No 1504 LTYADL SEQ ID No 1505 LTYAEL SEQ ID No 1506 LTYAQV SEQ ID No 1507 LTYARL SEQ ID No 1508 LTYCDL SEQ ID No 1509 LTYCGL SEQ ID No 1510 LTYCVL SEQ ID No 1511 LTYEEL SEQ ID No 1512 LTYEFL SEQ ID No 1513 LTYGEV SEQ ID No 1514 LTYGRL SEQ ID No 1515 LTYKAL SEQ ID No 1516 LTYLRL SEQ ID No 1517 LTYMTL SEQ ID No 1518 LTYNTL SEQ ID No 1519 LTYPGI SEQ ID No 1520 LTYQSV SEQ ID No 1521 LTYSSV SEQ ID No 1522 LTYTTV SEQ ID No 1523 LVYDAI SEQ ID No 1524 LVYDKL SEQ ID No 1525 LVYDLV SEQ ID No 1526 LVYENL SEQ ID No 1527 LVYGQL SEQ ID No 1528 LVYHKL SEQ ID No 1529 LVYQEV SEQ ID No 1530 LVYRKV SEQ ID No 1531 LVYRNL SEQ ID No 1532 LVYSEI SEQ ID No 1533 LVYTNV SEQ ID No 1534 LVYWEI SEQ ID No 1535 LVYWKL SEQ ID No 1536 LVYWRL SEQ ID No 1537 LWYEGL SEQ ID No 1538 LWYKYI SEQ ID No 1539 LWYNHI SEQ ID No 1540 LWYTMI SEQ ID No 1541 LYYCQL SEQ ID No 1542 LYYGDL SEQ ID No 1543 LYYKKV SEQ ID No 1544 LYYLLI SEQ ID No 1545 LYYPKV SEQ ID No 1546 LYYRRV SEQ ID No 1547 LYYSTI SEQ ID No 1548 LYYVRI SEQ ID No 1549 LYYVVI SEQ ID No 1550 SAYATL SEQ ID No 1551 SAYCPL SEQ ID No 1552 SAYPAL SEQ ID No 1553 SAYQAL SEQ ID No 1554 SAYQTI SEQ ID No 1555 SAYRSV SEQ ID No 1556 SAYTAL SEQ ID No 1557 SAYTPL SEQ ID No 1558 SAYVVL SEQ ID No 1559 SCYAAV SEQ ID No 1560 SCYCII SEQ ID No 1561 SCYCLL SEQ ID No 1562 SCYDFL SEQ ID No 1563 SCYEEL SEQ ID No 1564 SCYEKI SEQ ID No 1565 SCYHIL SEQ ID No 1566 SCYPYI SEQ ID No 1567 SCYRIL SEQ ID No 1568 SCYRTL SEQ ID No 1569 SDYCNL SEQ ID No 1570 SDYEDL SEQ ID No 1571 SDYENV SEQ ID No 1572 SDYESV SEQ ID No 1573 SDYFIV SEQ ID No 1574 SDYHTL SEQ ID No 1575 SDYLAI SEQ ID No 1576 SDYLDI SEQ ID No 1577 SDYLEL SEQ ID No 1578 SDYQDL SEQ ID No 1579 SDYQRL SEQ ID No 1580 SDYSVI SEQ ID No 1581 SDYTHL SEQ ID No 1582 SEYASV SEQ ID No 1583 SEYEEL SEQ ID No 1584 SEYFEL SEQ ID No 1585 SEYGEL SEQ ID No 1586 SEYITL SEQ ID No 1587 SEYKAL SEQ ID No 1588 SEYKEL SEQ ID No 1589 SEYKGI SEQ ID No 1590 SEYLAI SEQ ID No 1591 SEYLEI SEQ ID No 1592 SEYMVI SEQ ID No 1593 SEYQSI SEQ ID No 1594 SEYRPI SEQ ID No 1595 SEYSEI SEQ ID No 1596 SEYSSI SEQ ID No 1597 SEYTPI SEQ ID No 1598 SEYTYV SEQ ID No 1599 SFYAAL SEQ ID No 1600 SFYDSL SEQ ID No 1601 SFYKGL SEQ ID No 1602 SFYLYV SEQ ID No 1603 SFYNAV SEQ ID No 1604 SFYPSV SEQ ID No 1605 SFYQQI SEQ ID No 1606 SFYQQL SEQ ID No 1607 SFYSAL SEQ ID No 1608 SFYSDI SEQ ID No 1609 SFYSKL SEQ ID No 1610 SFYSRV SEQ ID No 1611 SFYWNV SEQ ID No 1612 SFYYLI SEQ ID No 1613 SGYAQL SEQ ID No 1614 SGYATL SEQ ID No 1615 SGYEKL SEQ ID No 1616 SGYQLV SEQ ID No 1617 SGYQRI SEQ ID No 1618 SGYRRL SEQ ID No 1619 SGYSHL SEQ ID No 1620 SGYSQL SEQ ID No 1621 SGYTLI SEQ ID No 1622 SGYTRI SEQ ID No 1623 SGYYRV SEQ ID No 1624 SHYADV SEQ ID No 1625 SHYFPL SEQ ID No 1626 SHYIDI SEQ ID No 1627 SHYKRL SEQ ID No 1628 SHYQVV SEQ ID No 1629 SIYAPL SEQ ID No 1630 SIYATL SEQ ID No 1631 SIYEEL SEQ ID No 1632 SIYEEV SEQ ID No 1633 SIYELL SEQ ID No 1634 SIYEVL SEQ ID No 1635 SIYGDL SEQ ID No 1636 SIYKKL SEQ ID No 1637 SIYLNI SEQ ID No 1638 SIYLVI SEQ ID No 1639 SIYRYI SEQ ID No 1640 SIYSWI SEQ ID No 1641 SKYKEI SEQ ID No 1642 SKYKIL SEQ ID No 1643 SKYKSL SEQ ID No 1644 SKYLAV SEQ ID No 1645 SKYLGV SEQ ID No 1646 SKYNIL SEQ ID No 1647 SKYQAV SEQ ID No 1648 SKYSDI SEQ ID No 1649 SKYSSL SEQ ID No 1650 SKYVGL SEQ ID No 1651 SKYVSL SEQ ID No 1652 SLYANI SEQ ID No 1653 SLYAQV SEQ ID No 1654 SLYAYI SEQ ID No 1655 SLYDDL SEQ ID No 1656 SLYDFL SEQ ID No 1657 SLYDNL SEQ ID No 1658 SLYDSI SEQ ID No 1659 SLYDYL SEQ ID No 1660 SLYEGL SEQ ID No 1661 SLYEHI SEQ ID No 1662 SLYELL SEQ ID No 1663 SLYHCL SEQ ID No 1664 SLYHKL SEQ ID No 1665 SLYIGI SEQ ID No 1666 SLYKKL SEQ ID No 1667 SLYKNL SEQ ID No 1668 SLYLAI SEQ ID No 1669 SLYLGI SEQ ID No 1670 SLYNAL SEQ ID No 1671 SLYNLL SEQ ID No 1672 SLYRNI SEQ ID No 1673 SLYSDV SEQ ID No 1674 SLYTCV SEQ ID No 1675 SLYTTL SEQ ID No 1676 SLYVAI SEQ ID No 1677 SLYVDV SEQ ID No 1678 SLYVSI SEQ ID No 1679 SLYYAL SEQ ID No 1680 SLYYNI SEQ ID No 1681 SLYYPI SEQ ID No 1682 SMYDGL SEQ ID No 1683 SMYEDI SEQ ID No 1684 SMYNEI SEQ ID No 1685 SMYQSV SEQ ID No 1686 SMYTWL SEQ ID No 1687 SMYVSI SEQ ID No 1688 SNYENL SEQ ID No 1689 SNYGSL SEQ ID No 1690 SNYGTI SEQ ID No 1691 SNYLVL SEQ ID No 1692 SNYQEI SEQ ID No 1693 SNYRLL SEQ ID No 1694 SNYRTL SEQ ID No 1695 SNYSDI SEQ ID No 1696 SNYSLL SEQ ID No 1697 SPYAEI SEQ ID No 1698 SPYATL SEQ ID No 1699 SPYEKV SEQ ID No 1700 SPYGDI SEQ ID No 1701 SPYGGL SEQ ID No 1702 SPYNTL SEQ ID No 1703 SPYPGI SEQ ID No 1704 SPYPGV SEQ ID No 1705 SPYQEL SEQ ID No 1706 SPYRSV SEQ ID No 1707 SPYSRL SEQ ID No 1708 SPYTDV SEQ ID No 1709 SPYTSV SEQ ID No 1710 SPYVVI SEQ ID No 1711 SQYCVL SEQ ID No 1712 SQYEAL SEQ ID No 1713 SQYKRL SEQ ID No 1714 SQYLAL SEQ ID No 1715 SQYLRL SEQ ID No 1716 SQYMHV SEQ ID No 1717 SQYSAV SEQ ID No 1718 SQYTSI SEQ ID No 1719 SQYWRL SEQ ID No 1720 SRYAEL SEQ ID No 1721 SRYATL SEQ ID No 1722 SRYESL SEQ ID No 1723 SRYGLL SEQ ID No 1724 SRYLSL SEQ ID No 1725 SRYMEL SEQ ID No 1726 SRYMRI SEQ ID No 1727 SRYPPV SEQ ID No 1728 SRYQAL SEQ ID No 1729 SRYQQL SEQ ID No 1730 SRYRFI SEQ ID No 1731 SRYRFV SEQ ID No 1732 SRYSAL SEQ ID No 1733 SRYSDL SEQ ID No 1734 SRYTGL SEQ ID No 1735 SRYVRL SEQ ID No 1736 SSYDEL SEQ ID No 1737 SSYEAL SEQ ID No 1738 SSYEIV SEQ ID No 1739 SSYEPL SEQ ID No 1740 SSYGRL SEQ ID No 1741 SSYGSI SEQ ID No 1742 SSYGSL SEQ ID No 1743 SSYHII SEQ ID No 1744 SSYHIL SEQ ID No 1745 SSYHKL SEQ ID No 1746 SSYHNI SEQ ID No 1747 SSYIKV SEQ ID No 1748 SSYNSV SEQ ID No 1749 SSYQEI SEQ ID No 1750 SSYRKV SEQ ID No 1751 SSYRRV SEQ ID No 1752 SSYSDI SEQ ID No 1753 SSYTPL SEQ ID No 1754 SSYTRL SEQ ID No 1755 SSYTSV SEQ ID No 1756 SSYTTI SEQ ID No 1757 SSYVKL SEQ ID No 1758 STYAEV SEQ ID No 1759 STYAGI SEQ ID No 1760 STYAHL SEQ ID No 1761 STYALV SEQ ID No 1762 STYAPI SEQ ID No 1763 STYDHV SEQ ID No 1764 STYDKV SEQ ID No 1765 STYDQV SEQ ID No 1766 STYDRI SEQ ID No 1767 STYEEL SEQ ID No 1768 STYEYL SEQ ID No 1769 STYILV SEQ ID No 1770 STYLPL SEQ ID No 1771 STYMAV SEQ ID No 1772 STYQTL SEQ ID No 1773 STYRKL SEQ ID No 1774 STYSQL SEQ ID No 1775 STYTSI SEQ ID No 1776 STYYQV SEQ ID No 1777 SVYATL SEQ ID No 1778 SVYCFL SEQ ID No 1779 SVYCNL SEQ ID No 1780 SVYDSV SEQ ID No 1781 SVYDTI SEQ ID No 1782 SVYEKV SEQ ID No 1783 SVYEML SEQ ID No 1784 SVYGSV SEQ ID No 1785 SVYPII SEQ ID No 1786 SVYQPI SEQ ID No 1787 SVYRKV SEQ ID No 1788 SVYSHL SEQ ID No 1789 SVYSRV SEQ ID No 1790 SVYTAL SEQ ID No 1791 SVYTEL SEQ ID No 1792 SVYWKV SEQ ID No 1793 SWYDSI SEQ ID No 1794 SWYFTV SEQ ID No 1795 SYYKAI SEQ ID No 1796 SYYLKL SEQ ID No 1797 SYYSFV SEQ ID No 1798 SYYVTI SEQ ID No 1799 VAYADL SEQ ID No 1800 VAYARI SEQ ID No 1801 VAYARV SEQ ID No 1802 VAYDQL SEQ ID No 1803 VAYGHV SEQ ID No 1804 VAYKQV SEQ ID No 1805 VAYKRL SEQ ID No 1806 VAYNLL SEQ ID No 1807 VAYQRV SEQ ID No 1808 VAYSGV SEQ ID No 1809 VAYSQV SEQ ID No 1810 VCYCIV SEQ ID No 1811 VCYGLV SEQ ID No 1812 VCYGRL SEQ ID No 1813 VCYIVV SEQ ID No 1814 VCYLLV SEQ ID No 1815 VDYDCI SEQ ID No 1816 VDYDFL SEQ ID No 1817 VDYFTI SEQ ID No 1818 VDYFVL SEQ ID No 1819 VDYGEL SEQ ID No 1820 VDYILV SEQ ID No 1821 VDYIQV SEQ ID No 1822 VDYKNI SEQ ID No 1823 VDYMSI SEQ ID No 1824 VDYNLV SEQ ID No 1825 VDYPDV SEQ ID No 1826 VDYSDL SEQ ID No 1827 VDYSSV SEQ ID No 1828 VDYTTL SEQ ID No 1829 VDYVDV SEQ ID No 1830 VDYVGV SEQ ID No 1831 VDYVIL SEQ ID No 1832 VDYVQV SEQ ID No 1833 VEYAPL SEQ ID No 1834 VEYDPL SEQ ID No 1835 VEYGTI SEQ ID No 1836 VEYHRL SEQ ID No 1837 VEYLEV SEQ ID No 1838 VEYQLL SEQ ID No 1839 VEYRPL SEQ ID No 1840 VEYSSI SEQ ID No 1841 VEYSTV SEQ ID No 1842 VFYAEI SEQ ID No 1843 VFYLAV SEQ ID No 1844 VFYRQV SEQ ID No 1845 VFYVGV SEQ ID No 1846 VFYYVI SEQ ID No 1847 VFYYVL SEQ ID No 1848 VGYETI SEQ ID No 1849 VHYALL SEQ ID No 1850 VHYARL SEQ ID No 1851 VHYETL SEQ ID No 1852 VHYGGV SEQ ID No 1853 VHYHSL SEQ ID No 1854 VHYIPV SEQ ID No 1855 VHYKEI SEQ ID No 1856 VHYLQV SEQ ID No 1857 VHYNSL SEQ ID No 1858 VHYQSV SEQ ID No 1859 VHYRSL SEQ ID No 1860 VIYAQL SEQ ID No 1861 VIYDRL SEQ ID No 1862 VIYENV SEQ ID No 1863 VIYEPL SEQ ID No 1864 VIYERL SEQ ID No 1865 VIYIDV SEQ ID No 1866 VIYKKI SEQ ID No 1867 VIYKRI SEQ ID No 1868 VIYPFL SEQ ID No 1869 VIYPNI SEQ ID No 1870 VIYSDL SEQ ID No 1871 VIYSML SEQ ID No 1872 VIYSSV SEQ ID No 1873 VIYSWI SEQ ID No 1874 VKYADI SEQ ID No 1875 VKYARL SEQ ID No 1876 VKYATL SEQ ID No 1877 VKYEGL SEQ ID No 1878 VKYGDL SEQ ID No 1879 VKYGSV SEQ ID No 1880 VKYLLV SEQ ID No 1881 VKYNPV SEQ ID No 1882 VKYPPI SEQ ID No 1883 VKYQRL SEQ ID No 1884 VKYQVI SEQ ID No 1885 VKYSEV SEQ ID No 1886 VKYSNV SEQ ID No 1887 VKYSRL SEQ ID No 1888 VKYSTL SEQ ID No 1889 VKYVDL SEQ ID No 1890 VLYADI SEQ ID No 1891 VLYAML SEQ ID No 1892 VLYASV SEQ ID No 1893 VLYCLL SEQ ID No 1894 VLYCLV SEQ ID No 1895 VLYCVL SEQ ID No 1896 VLYDCL SEQ ID No 1897 VLYFHI SEQ ID No 1898 VLYFTV SEQ ID No 1899 VLYGDL SEQ ID No 1900 VLYGQL SEQ ID No 1901 VLYPMV SEQ ID No 1902 VLYPRL SEQ ID No 1903 VLYPRV SEQ ID No 1904 VLYSEL SEQ ID No 1905 VLYSRV SEQ ID No 1906 VLYTAV SEQ ID No 1907 VLYTIL SEQ ID No 1908 VMYDAV SEQ ID No 1909 VNYESI SEQ ID No 1910 VNYSAL SEQ ID No 1911 VNYSKI SEQ ID No 1912 VNYSSI SEQ ID No 1913 VPYALL SEQ ID No 1914 VPYDTL SEQ ID No 1915 VPYEDV SEQ ID No 1916 VPYEEL SEQ ID No 1917 VPYKTI SEQ ID No 1918 VPYLRV SEQ ID No 1919 VPYNDL SEQ ID No 1920 VPYPAL SEQ ID No 1921 VPYQEL SEQ ID No 1922 VPYRLL SEQ ID No 1923 VPYSEL SEQ ID No 1924 VPYTLL SEQ ID No 1925 VPYTPL SEQ ID No 1926 VPYTTL SEQ ID No 1927 VPYVEL SEQ ID No 1928 VPYVMV SEQ ID No 1929 VPYVSL SEQ ID No 1930 VQYKAV SEQ ID No 1931 VQYKEI SEQ ID No 1932 VQYNIV SEQ ID No 1933 VQYRPV SEQ ID No 1934 VQYSQI SEQ ID No 1935 VQYSTV SEQ ID No 1936 VQYTEV SEQ ID No 1937 VQYYNI SEQ ID No 1938 VRYARL SEQ ID No 1939 VRYDNL SEQ ID No 1940 VRYGRI SEQ ID No 1941 VRYKKL SEQ ID No 1942 VRYKRV SEQ ID No 1943 VRYLDV SEQ ID No 1944 VRYRTI SEQ ID No 1945 VRYSDI SEQ ID No 1946 VRYTQL SEQ ID No 1947 VRYVCL SEQ ID No 1948 VSYAEL SEQ ID No 1949 VSYASV SEQ ID No 1950 VSYEPI SEQ ID No 1951 VSYGDI SEQ ID No 1952 VSYIGL SEQ ID No 1953 VSYILV SEQ ID No 1954 VSYMML SEQ ID No 1955 VSYNNI SEQ ID No 1956 VSYNNL SEQ ID No 1957 VSYQEI SEQ ID No 1958 VSYQPI SEQ ID No 1959 VSYSAV SEQ ID No 1960 VSYSFL SEQ ID No 1961 VSYSLV SEQ ID No 1962 VSYSPV SEQ ID No 1963 VSYTML SEQ ID No 1964 VSYTNL SEQ ID No 1965 VSYTPL SEQ ID No 1966 VSYVKI SEQ ID No 1967 VSYVLL SEQ ID No 1968 VTYADL SEQ ID No 1969 VTYAEL SEQ ID No 1970 VTYAEV SEQ ID No 1971 VTYAKV SEQ ID No 1972 VTYAPV SEQ ID No 1973 VTYAQL SEQ ID No 1974 VTYATL SEQ ID No 1975 VTYATV SEQ ID No 1976 VTYGNI SEQ ID No 1977 VTYITI SEQ ID No 1978 VTYQII SEQ ID No 1979 VTYQIL SEQ ID No 1980 VTYQLL SEQ ID No 1981 VTYSAL SEQ ID No 1982 VTYSTL SEQ ID No 1983 VTYTLL SEQ ID No 1984 VTYTQL SEQ ID No 1985 VTYVNL SEQ ID No 1986 VVYADI SEQ ID No 1987 VVYEDV SEQ ID No 1988 VVYFCL SEQ ID No 1989 VVYKTL SEQ ID No 1990 VVYQKL SEQ ID No 1991 VVYSEV SEQ ID No 1992 VVYSQV SEQ ID No 1993 VVYSVV SEQ ID No 1994 VVYTVL SEQ ID No 1995 VVYYRI SEQ ID No 1996 VYYHWL SEQ ID No 1997 VYYLPL SEQ ID No 1998

In some embodiments, the ITIM, or at least one of the ITIMs when several ITIMs are present in the intracellular domain is selected from LSYRSL, LPYYDL, LLYSRL, LIYTLL, LLYADL, ISYTTL, VTYSAL, IHYSEL, VDYVIL, LHYASL, LDYDYL, VDYDFL, VTYSTL, IIYSEV, LEYLCL, VLYGQL, VPYTPL, ISYPML, VSYTNL, LLYEMV, VDYNLV, ITYFAL, VHYQSV, VPYVMV, IPYRTV, IAYSLL, VCYGRL, LKYLYL, LLYEHV, ITYSLL, VLYSEL, IWYNIL, ISYKGL, IDYYNL, LEYLQL, LKYRGL, VLYASV, LQYLSL, LFYRHL, VQYKAV, LSYSSL, LSYTKV, VQYSTV, VKYNPV, VVYSEV, LEYVSV, LAYHTV, VQYLRL, VTYTQL, IVYTEL, IVYAEL, VTYAQL, ILYTEL, ITYAAV, VIYIDV, VTYAEV, VTYAPV, VTYAKV, VTYARL, ILYHTV, VLYAML, VIYAQL, LVYENL, LCYADL, ISYASL, LTYVLL, VTYVNL, VRYSIV, VFYRQV, LKYMEV, VDYGEL, LSYMDL, VLYTAV, VQYTEV, IVYASL, VEYLEV, LEYVDL, ITYADL, LTYADL, VIYENV, LAYYTV, VSYSAV, LVYDKL, LNYMVL, LNYACL, LDYINV, LHYATL, LHYAVL, IQYAPL, IQYASL, LLYLLL, VVYSQV, VIYSSV, VVYYRV, VPYVEL, LDYDKL, LSYPVL, VAYSQV, LFYWDV, LIYSQV, or LDYEFL.

In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 1, 2, 3, 4 or 5. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 1, 2, 3, 4 or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 1, 2, 3, 4 or 5. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

In some embodiments, n is 1 and m is 1.

In some embodiments, n is 1 and m is 1 and p is 1 to 10.

In some embodiments, n is 1 and m is 1 and p is 1.

In some embodiments, n is 0 and m is 1 and p is 1 to 20.

In some embodiments, n is 0, m is 1 to 6 and p is 1.

In some embodiments, n is 0, m is 1 and p is 1.

In some embodiments, n is 0, m is 2 and p is 1.

In some embodiments, n is 0, m is 3 and p is 1.

In some embodiments, n is 0, m is 4 and p is 1.

In some embodiments, n is 0, m is 5 and p is 1.

In some embodiments, n is 0, m is 6 and p is 1.

In some embodiments, n is 0, m is 1 to 6 and p is 1 and ITSM is TEYATI.

In some embodiments, n is 0, m is 1 to 6 and p is 1 and ITSM is TEYSEI.

In some embodiments, n is 0, m is 1 to 6 and p is 1 and ITSM is TVYSEV.

In some embodiments, n is 1, m is 1 and p is 1 to 5.

In some embodiments, n is 1, m is 1 and p is 1.

In some embodiments, n is 1, m is 1 and p is 2.

In some embodiments, n is 1, m is 1 and p is 3.

In some embodiments, n is 1, m is 1 and p is 4.

In some embodiments, n is 1, m is 1 and p is 5.

In some embodiments, n is 1, m is 1 and p is 1 to 5 and ITIM is VDYGEL and ITSM is TEYATI.

In some embodiments, n is 1, m is 1 and p is 1 to 5 and ITIM is LX₆YAX₈L wherein X₆ is selected from H or Q and X₈ is V or S, and ITSM is TEYSEI.

In some embodiments, n is 1, m is 1 and p is 1 to 5 and ITIM is LX₆YAX₈L wherein X₆ is selected from H or Q and X₈ is V or S, and ITSM is TEYASI.

In some embodiments, n is 1, m is 1 and p is 1 to 5 and ITIM is LX₆YAX₈L wherein X₆ is selected from H or Q and X₈ is V or S, and ITSM is TVYSEV.

In some embodiments, the intracellular domain comprises several ITSMs having the same amino acid sequence.

In some embodiments, the intracellular domain comprises several ITSMs having different amino acid sequences.

In some embodiments, the intracellular domain comprises several ITIMs having the same amino acid sequence.

In some embodiments, the intracellular domain comprises several ITIMs having different amino acid sequences.

In some embodiments, the intracellular domain of the NCAR is selected from SEQ ID No 2000, SEQ ID No 2001, SEQ ID No 2002, SEQ ID No 2003, SEQ ID No 2004, SEQ ID No 2005, SEQ ID No 2006, SEQ ID No 2007, SEQ ID No 2008, SEQ ID No 2009, SEQ ID No 2010, SEQ ID No 2011, SEQ ID No 2012, SEQ ID No 2013, SEQ ID No 2014, SEQ ID No 2015, SEQ ID No 2016 and SEQ ID No 2017.

TABLE 1 Naturally occurring N-terminal flanking region of ITIM.*ITSM intracellular domains varying in length from 1-520 (Table 1 comprises SEQ ID No 1 to SEQ ID No 36) N ELFANKRKYT SEQ ID No 1 RKRNNSRLGNG SEQ ID No 2 YRHRKKRNGLT SEQ ID No 3 YKMYGSEMLHKRDPLDEDEDTD SEQ ID No 4 LRKRRDSLSLSTQRTQGPAESARN SEQ ID No 5 WRMMKYQQKAAGMSPEQVLQPLEGD SEQ ID No 6 CSRAARGTIGARRTGQPLKEDPSAVPVFS SEQ ID No 7 RIRQKKAQGSTSSTRLHEPEKNAREITQDTND SEQ ID No 8 NNSYQEIEEDADVEWKFARAKLWLSYFDEGRTLPAPFNLVPSPK SEQ ID No 9 WLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPS SEQ ID No 10 SNKCDVVVVGGGISGMAAAKLLHDSGLNVVVLEARDRVGGRTYTLRNQK SEQ ID No 11 KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPT SEQ ID No 12 VEMDEE RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAGPI SEQ ID No 13 SEDEQE KARRKQAAGRPEKMDDEDPIMGTITSGSRKKPWPDSPGDQASPPGDAP SEQ ID No 14 PLEEQKE KICRKEARKRAAAEQDVPSTLGPISQGHQHECSAGSSQDHPPPGAATYT SEQ ID No 15 PGKGEEQE MENQEKASIAGHMFDVVVIGGGISGLSAAKLLTEYGVSVLVLEARDRVGG SEQ ID No 16 RTYTIRNEH VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQP SEQ ID No 17 PPASARSSVGEGE KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDD SEQ ID No 18 VRNHAMKPINDNKEPLNSD VRLRLQKHRPPADPCRGETETMNNLANCQREKDISVSIIGATQIKNTNKKA SEQ ID No 19 DFHGDHSADKNGFKARYPA RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN SEQ ID No 20 DPDLCFRMQEGSEVYSNPCLEENKPG QSVFNKRKSRVRHYLVKCPQNSSGETVTSVTSLAPLQPKKGKRQKEKPDI SEQ ID No 21 PPAVPAKAPIAPTFHKPKLLKPQRKVTLPKIAEEN MSDKMSSFLHIGDICSLYAEGSTNGFISTLGLVDDRCVVQPETGDLNNPP SEQ ID No 22 KKFRDCLFKLCPMNRYSAQKQFWKAAKPGANSTTDAVLLNKLHHAADLE KKQNETENRKLLGTV MTEKMSSFLYIGDIVSLYAEGSVNGFISTLGLVDDRCVVHPEAGDLANPPK SEQ ID No 23 KFRDCLFKVCPMNRYSAQKQYWKAKQAKQGNHTEAALLKKLQHAAELE QKQNESENKKLLGEI MSEMSSFLHIGDIVSLYAEGSVNGFISTLGLVDDRCVVEPAAGDLDNPPKK SEQ ID No 24 FRDCLFKVCPMNRYSAQKQYWKAKQTKQDKEKIADVVLLQKLQHAAQME QKQNDTENKKVHGDV NCVSCCKDPEIDFKEFEDNFDDEIDFTPPAEDTPSVQSPAEVFTLSVPNIS SEQ ID No 25 LPAPSQFQPSVEGLKSQVARHSLNYIQEIGNGWFGKVLLGEIYTGTSVAR VIVKELKASANPKEQDTFLKNGEPYYILQHPNILQCVGQCVEA KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNKL SEQ ID No 26 EDVVIDRNLLILGKILGEGEF GSVMEGNLKQEDGTSLKVAVKTMKLDNSSQREIEEFLSEAACMKDFSHP NVIRLLGVCIEMSSQGIPKPMVILPFMKYGDLHTY HRRKKETRYGEVFEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEEL SEQ ID No 27 KEKLRDVMVDRHKVALGKTLGEGEFGAVMEGQLNQDDSILKVAVKTMKIA ICTRSELEDFLSEAVCMKEFDHPNVMRLIGVCFQGSERESFPAPVVILPFM KHGDLHSF MSGGASATGPRRGPPGLEDTTSKKKQKDRANQESKDGDPRKETGSRYV SEQ ID No 28 AQAGLEPLASGDPSASASHAAGITGSRHRTRLFFPSSSGSASTPQEEQTK EGACEDPHDLLATPTPELLLDWRQSAEEVIVKLRVGVGPLQLEDVDAAFT DTDCVVRFAGGQQWGG AYKRKSRESDLTLKRLQMQMDNLESRVALECKEAFAELQTDIHELTSDLD SEQ ID No 29 GAGIPFLDYRTYTMRVLFPGIEDHPVLRDLEVPGYRQERVEKGLKLFAQLI NNKVFLLSFIRTLESQRSFSMRDRGNVASLIMTVLQSKLEYATDVLKQLLA DLIDKNLESKNHPKLLLRRTESVAEKMLTNWFTF YKRKTQDADRTLKRLQLQMDNLESRVALECKEAFAELQTDINELTNHMDE SEQ ID No 30 VQIPFLDYRTYAVRVLFPGIEAHPVLKELDTPPNVEKALRLFGQLLHSRAFV LTFIHTLEAQSSFSMRDRGTVASLTMVALQSRLDYATGLLKQLLADLIEKNL ESKNHPKLLLRRTESVAEKMLTNWFTFLLHKFLKECAGEPLF RWHCPRRLLGACWTLNGQEEPVSQPTPQLENEVSRQHLPATLPEMVAF SEQ ID No 31 YQELHTPTQGQTMVRQLMHKLLVFSAREVDHRGGCLMLQDTGISLLIPPG AVAVGRQERVSLILVWDLSDAPSLSQAQGLVSPVVACGPHGASFLKPCTL TFKHCAEQPSHARTYSSNTTLLDAKVWRPLGRPGAHASRDECRIHLSHF KQKPRYEIRWRVIESISPDGHEYIYVDPMQLPYDSRWEFPRDGLVLGRVL SEQ ID No 32 GSGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQALMSELKIM THLGPHLNIVNLLGACTKSGPIYIITEYCFYGDLVNYLHKNRDSFLSHHPEK PKKELDIFGLNPADESTRSYVILSFENNGDYMDMKQADTTQYVPMLERKEV MFNYTFQQVQEHTDQIWKFQRHDLIEEYHGRPAAPPPFILLSHLQLFIKRV SEQ ID No 33 VLKTPAKRHKQLKNKLEKNEEAALLSWEIYLKENYLQNRQFQQKQRPEQK IEDISNKVDAMVDLLDLDPLKRSGSMEQRLASLEEQVAQTAQALHWIVRTL RASGFSSEADVPTLASQKAAEEPDAEPGGRKKTEEPGDSYHVNARHLLY PNCPVTRFPVPNEKVPWETEFLIYDPPFYTAERKDAAAMDPMGDTLEPLST CCDCGGAPRSAAGFEPVPECSDGAIHSWAVEGPQPEPRDITTVIPQIPPD SEQ ID No 34 NANIIECIDNSGVYTNEYGGREMQDLGGGERMTGFELTEGVKTSGMPEIC QEYSGTLRRNSMRECREGGLNMNFMESYFCQKAYAYADEDEGRPSNDC LLIYDIEGVGSPAGSVGCCSFIGEDLDDSFLDTLGPKFKKLADISLGKESYP DLDPSWPPQSTEPVCLPQETEPVVSGHPPISPHFGTTTVISESTYPSGPG VLHPKPILDP MADGGEGEDEIQFLRTDDEVVLQCTATIHKEQQKLCLAAEGFGNRLCFLE SEQ ID No 35 STSNSKNVPPDLSICTFVLEQSLSVRALQEMLANTVEKSEGQVDVEKWKF MMKTAQGGGHRTLLYGHAILLRHSYSGMYLCCLSTSRSSTDKLAFDVGL QEDTTGEACWWTIHPASKQRSEGEKVRVGDDLILVSVSSERYLHLSYGN GSLHVDAAFQQTLWSVAPISSGSEAAQGYLIGGDVLRLLHGHMDECLTVP SGEHGEEQRRTVHYEGGAVSVHARSLWRLETLRVAWSGSHIRWGQPFR LRHVTTGKYLSLMEDKNLLLMDKEKADVKSTAFTFRSSKEKLDVGVRKEV DGMGTSEIKYGDSVCYIQHVDTGLW MGDAEGEDEVQFLRTDDEVVLQCSATVLKEQLKLCLAAEGFGNRLCFLE SEQ ID No 36 PTSNAQNVPPDLAICCFVLEQSLSVRALQEMLANTVEAGVESSQGGGHR TLLYGHAILLRHAHSRMYLSCLTTSRSMTDKLAFDVGLQEDATGEACWWT MHPASKQRSEGEKVRVGDDIILVSVSSERYLHLSTASGELQVDASFMQTL WNMNPICSRCEEGFVTGGHVLRLFHGHMDECLTISPADSDDQRRLVYYE GGAVCTHARSLWRLEPLRISWSGSHLRWGQPLRVRHVTTGQYLALTEDQ GLVVVDASKAHTKATSFCFRISKEKLDVAPKRDVEGMGPPEIKYGESLCF VQHVASGLWLTYAAPDPKALRLGVLKKKAMLHQEGHMDDALSLTRCQQE ESQAARMIHSTNGLYNQFIKSLDSFSGKPRGSGPPAGTALPIEGVILSLQD LIIYFEPPSEDLQHEEKQSKLRSLRNRQSLFQEEGMLSMVLNCIDRLNVYT TAAHFAEFAGEEAAESWKEIVN

TABLE 2 Examples of intracellular domains of known inhibitory receptors CTLA4 AVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN (SEQ ID No 37) LAG3 HLWRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPE QL (SEQ ID No 38) HAVCR2 FKWYSHSKEKIQNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNE (TIM3) YYCYVSSRQQPSQPLGCRFAMP (SEQ ID No 39) LAIR1 HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDRETDT SALAAGSSQEVTYAQLDHWALTQRTARAVSPQSTKPMAESITYAAVARH (SEQ ID No 40) KIR2DL2 HRWCSNKKNAAVMDQESAGNRTANSEDSDEQDPQEVTYTQLNHCVFTQRKI TRPSQRPKTPPTDIIVYAELPNAESRSKVVSCP (SEQ ID No 41) LILRB1 LRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEENLY AAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEF LDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPS PAVPSIYATLAIH (SEQ ID No 2021) TIGIT LTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCGEQ RGEDCAELHDYFNVLSYRSLGNCSFFTETG (SEQ ID No 2022) CEACAM1 HFGKTGRASDQRDLTEHKPSVSNHTQDHSNDPPNKMNEVTYSTLNFEAQQPT QPTSASPSLTATEIIYSEVKKQ (SEQ ID No 2023) CSF1R KYKQKPKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNLQFGKTLGAG AFGKVVEATAFGLGKEDAVLKVAVKMLKSTAHADEKEALMSELKIMSHLGQHE NIVNLLGACTHGGPVLVITEYCCYGDLLNFLRRKAEAMLGPSLSPGQDPEGGV DYKNIHLEKKYVRRDSGFSSQGVDTYVEMRPVSTSSNDSFSEQDLDKEDGRP LELRDLLHFSSQVAQGMAFLASKNCIHRDVAARNVLLTNGHVAKIGDFGLARDI MNDSNYIVKGNARLPVKWMAPESIFDCVYTVQSDVWSYGILLWEIFSLGLNPY PGILVNSKFYKLVKDGYQMAQPAFAPKNIYSIMQACWALEPTHRPTFQQICSFL QEQAQEDRRERDYTNLPSSSRSGGSGSSSSELEEESSSEHLTCCEQGDIAQP LLQPNNYQFC ((SEQ ID No 2024) CD5 KKLVKKFRQKKQRQWIGPTGMNQNMSFHRNHTATVRSHAENPTASHVDNEY SQPPRNSHLSAYPALEGALHRSSMQPDNSSDSDYDLHGAQRL ((SEQ ID No 2025) CD96 RKWCQYQKEIMERPPPFKPPPPPIKYTCIQEPNESDLPYHEMETL (SEQ ID No 2026) CD22 KLQRRWKRTQSQQGLQENSSGQSFFVRNKKVRRAPLSEGPHSLGCYNPMME DGISYTTLRFPEMNIPRTGDAESSEMQRPPPDCDDTVTYSALHKRQVGDYENV IPDFPEDEGIHYSELIQFGVGERPQAQENVDYVILKH (SEQ ID No 2027)

TABLE 3 Examples of naturally occurring N-terminal flanking regions of ITIM only intracellular domains varying in length from 0 to 4211 (Table 3 comprises SEQ ID No 42 to SEQ ID No 351) K V Q V T F Y LL QP EH NL KW LV NP TF RL LNP KCP ETL RRA MAQ RRRP SEQ ID No 42 MSEE SEQ ID No 43 MTSE SEQ ID No 44 DRYL SEQ ID No 45 MTDS SEQ ID No 46 AAKP SEQ ID No 47 QHFS SEQ ID No 48 MKPK SEQ ID No 49 IAAL SEQ ID No 50 CLNP SEQ ID No 51 QKVL SEQ ID No 52 DRYQS SEQ ID No 53 LKAKD SEQ ID No 54 DRYYA SEQ ID No 55 MSYYG SEQ ID No 56 SSSKP SEQ ID No 57 LKIRH SEQ ID No 58 DVRHV SEQ ID No 59 DRFYA SEQ ID No 60 EGWRI SEQ ID No 61 SDIKR SEQ ID No 62 LHHKKY SEQ ID No 63 TVDRYL SEQ ID No 64 SSPTFR SEQ ID No 65 WRRAGH SEQ ID No 66 YRVDLV SEQ ID No 67 NSFDLA SEQ ID No 68 YRSGIT SEQ ID No 69 YRLGLT SEQ ID No 70 QHIMAI SEQ ID No 71 NSCANP SEQ ID No 72 RRFCAT SEQ ID No 73 GDMANNS SEQ ID No 74 MAYQSLR SEQ ID No 75 TARNLTV SEQ ID No 76 MERAEEP SEQ ID No 77 SMDRFLA SEQ ID No 78 LRLAAAP SEQ ID No 79 LRLFAAP SEQ ID No 80 KRLIALS SEQ ID No 81 YSNSSVNP SEQ ID No 82 YANSCVNP SEQ ID No 83 KLSPRVKR SEQ ID No 84 KIRLRCQS SEQ ID No 85 SCDLLTAF SEQ ID No 86 MASESSPL SEQ ID No 87 KTANEGGS SEQ ID No 88 DFAKEGHS SEQ ID No 89 DHVRRKDS SEQ ID No 90 DNVKKENS SEQ ID No 91 VMWKHRYQ SEQ ID No 92 KMYYSRRG SEQ ID No 93 DRYIAIRIP SEQ ID No 94 DRYLAICVP SEQ ID No 95 DRYLRVKLT SEQ ID No 96 DRYIGVSYP SEQ ID No 97 DRYIGVRYS SEQ ID No 98 DRYVGVRHS SEQ ID No 99 DRYLAVTNP SEQ ID No 100 MPFHPVTAA SEQ ID No 101 DRYISIHRP SEQ ID No 102 MQLKILVSA SEQ ID No 103 WKQRRAKEK SEQ ID No 104 DRFIAVVHP SEQ ID No 105 DRYIAITKP SEQ ID No 106 NRYCYICHS SEQ ID No 107 DRYLAITKP SEQ ID No 108 DRYCAVMDP SEQ ID No 109 DRYISIFYA SEQ ID No 110 DRYITIFHA SEQ ID No 111 NRYCYICHS SEQ ID No 112 WKKICNKSS SEQ ID No 113 WCYRKRYFV SEQ ID No 114 AHSNSCLNP SEQ ID No 115 PVFYKLGIT SEQ ID No 116 KFHRSRRLLG SEQ ID No 117 VDRYLRVKIP SEQ ID No 118 FERSCRKENM SEQ ID No 119 LPSIYLVFLI SEQ ID No 120 SSKTFQTWQS SEQ ID No 121 IDRYIAVCHP SEQ ID No 122 SFCLRNLFFP SEQ ID No 123 LLKTAKEGGS SEQ ID No 124 MWRNSKVMNI SEQ ID No 125 VEKKLFIHEYI SEQ ID No 126 RKRNNSRLGNG SEQ ID No 127 QRITVHVTRRP SEQ ID No 128 MEAAHAKTTEEC SEQ ID No 129 MARISFSYLCPA SEQ ID No 130 CCKRQKGKPKRK SEQ ID No 131 MTGDKGPQRLSG SEQ ID No 132 PDIPQSVKNKVLE SEQ ID No 133 KIFKIDIVLWYRD SEQ ID No 134 TEYVVRLWSAGCR SEQ ID No 135 QSKSELSHYTFYF SEQ ID No 136 SIVAYKQVPL SEQ ID No 137 SLDFFGSQNTQDD SEQ ID No 138 LWLHNGRSCFGVNR SEQ ID No 139 RFLRLNLKPDLSDT SEQ ID No 140 REHQRSGSYHVREE SEQ ID No 141 MITLTELKCLADAQ SEQ ID No 142 YNLTRLCRWDKRLL SEQ ID No 143 AFMNENFKKNVLSA SEQ ID No 144 MIYRLAQAEERQQLE SEQ ID No 145 KFRKNFWKLVKDIGC SEQ ID No 146 ALALAALAAVEPACG SEQ ID No 147 KKIAAATETAAQENA SEQ ID No 148 YRKVSKAEEAAQENA SEQ ID No 149 LKDFSILLMEGVPKS SEQ ID No 150 TVATAVEQYVPSEKL SEQ ID No 151 MGRQKELVSRCGEMLH SEQ ID No 152 CKRRRGQSPQSSPDLP SEQ ID No 153 LLEGVHLFLTARNLTV SEQ ID No 154 EERERKHHLKHGPNAP SEQ ID No 155 PLTHRLLCSEEPPRLH SEQ ID No 156 LYLLVRKHINRAHTAL SEQ ID No 157 KLPLWGQPSDQNCYDD SEQ ID No 158 MYRLKVLQMRLRSAITG SEQ ID No 159 SMRGTICNPGPRKSMSK SEQ ID No 160 RILVRKLEPAQGSLHTQ SEQ ID No 161 SRYATLMQKDSSQETT SEQ ID No 162 SSHFGCQLVCCQSSNVS SEQ ID No 163 RILMRKLRTQETRGNEV SEQ ID No 164 RILLQKLRPPDIRKSDS SEQ ID No 165 RILLQKLTSPDVGGNDQ SEQ ID No 166 RSVRPCFTQAAFLKSKYW SEQ ID No 167 RSGRGRKLSGDQITLPTT SEQ ID No 168 MAAENEASQESALGAYSP SEQ ID No 169 TAHVFSCLSLRLRAAFFY SEQ ID No 170 NPFIYSRNSAGLRRKVLWC SEQ ID No 171 NNESSNNPSSIASFLSSITY SEQ ID No 172 TPQLFINYKLKSVAHLPWRM SEQ ID No 173 WRLKPSADCGPFRGLPLFIH SEQ ID No 174 NIPLLFYHLWRYFHRPADGSE SEQ ID No 175 SQVTKSSPEQSYQGDMYPTRG SEQ ID No 176 CCSALQKRCRKCFNKDSTEAT SEQ ID No 177 CQRLAARLGVVTGKDLGEVCH SEQ ID No 178 QVFRNISGKQSSLPAMSKVRR SEQ ID No 179 GGRREGESWNWAWVLSTRLARH SEQ ID No 180 YKMYGSEMLHKRDPLDEDEDTD SEQ ID No 181 HMYRERGGELLVHTGFLGSSQDR SEQ ID No 182 RKWCQYQKEIMERPPPFKPPPPP SEQ ID No 183 HNKRKIFLLVQSRKWRDGLCSKT SEQ ID No 184 RAARRRPEHLDTPDTPPRSQAQE SEQ ID No 185 NGTCFTAGRLIYVAGREGHMLKV SEQ ID No 186 DANYEMPGETLKVRYWPRDSWPVG SEQ ID No 187 ARSQMARNIWYFVVS SEQ ID No 188 LRKRRDSLSLSTQRTQGPAESARN SEQ ID No 189 DAASEIPEQGPVIKFWPNEKWAFIG SEQ ID No 190 WGYKNYREQRQLPQGDYVKKPGDGD SEQ ID No 191 TSYYSFVSHLRKIRTCTSIMEKD SEQ ID No 192 LIVRALIYKDLDNSPLRRK SEQ ID No 193 DHWALTQRTARAVSPQSTKPMAES SEQ ID No 194 HHNKRKIIAFVLEGKRSKVTRRPKA SEQ ID No 195 EWKSPFGLTPKGRNRSKVFSFSSALN SEQ ID No 196 YFLGRLVPRGRGAAEAATRKQRITETE SEQ ID No 197 QATACRTCHRQQQPAACRGFARVARTIL SEQ ID No 198 NKFSKYYQKQKDIDVDQCSEDAPEKCHE SEQ ID No 199 SKCSREVLWHCHLCPSSTEHASASANGH SEQ ID No 200 DMGSSDGETTHDSQITQEAVPKSLGASE SEQ ID No 201 CSRAARGTIGARRTGQPLKEDPSAVPVFS SEQ ID No 202 SVQKLSEFLSSAEIREEQCAPHEPTPQGPA SEQ ID No 203 KCYKIEIMLFYRNHFGAEELDGDNKDYDAY SEQ ID No 204 KCYNIELMLFYRQHFGADETNDDNKEYDAY SEQ ID No 205 GWKLRSYKTLFDAAETMVSLQLGIFNYEEV SEQ ID No 206 SSFSSCKDVTAEENNEAKNLQLAVARIKKG SEQ ID No 207 MRTKAAGCAERRPLQPRTEAAAAPAGRAMP SEQ ID No 208 RKRWQNEKLGLDAGDEYEDENLYEGLNLDDC SEQ ID No 209 MASHEVDNAELGSASAHGTPGSEAGPEELNT SEQ ID No 210 NGHPTSNAALFFIERRPHHWPAMKFRSHPDH SEQ ID No 211 ALLNNIIEIRLDAKKFVTELRRPVAVRAKDIG SEQ ID No 212 PETKGQSLAEIDQQFQKRRFTLSFGHRQNSTG SEQ ID No 213 PETKGKKLEEIESLFDNRLCTCGTSDSDEGRY SEQ ID No 214 YNLMSQKFRAAFRKLCNCKQKPTEKPANYSVA SEQ ID No 215 NYIFFGRGPQRQKKAAEKAASANNEKMRLDVNK SEQ ID No 216 DLNESANSTAQYASNAWFAAASSEPEEGISVFE SEQ ID No 217 DLNESANSTAQYASNAWFAAASSEPEEGISVFE SEQ ID No 218 SYQQKKFCFSIQQGLNADYVKGENLEAVVCEEPQ SEQ ID No 219 MDGSGERSLPEPGSQSSAASDDIEIVVNVGGVRQ SEQ ID No 220 RWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQE SEQ ID No 221 MFCSEKKLREVERIVKANDREYNEKFQYADNRIHT SEQ ID No 222 TQFSETKQRESQLMREQRVRFLSNASTLASFSEPG SEQ ID No 223 NWLNPPRLQMGSMTSTTLYNSMWFVYGSFVQQGGE SEQ ID No 224 CFYIKKINPLKEKSIILPKSLISVVRSATLETKPE SEQ ID No 225 HRWCANKKNAVVMDQEPAGNRTVNREDSDEQDPQE SEQ ID No 226 NYYSSCRKPTTTKKTTSLLHPDSSRWIPERISLQAP SEQ ID No 227 HLTALFLTVYEWRSPYGLTPRGRNRSTVFSYSSALN SEQ ID No 228 YFFIRTLQAHHDRSERESPFSGSSRQPDSLSSIENA SEQ ID No 229 LHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQE SEQ ID No 230 HYLRFQRKSIDGSFGSNDGSGNMVASHPIAASTPEG SEQ ID No 231 RWWNQYENLPWPDRLMSLVSGFVEGKDEQGRLLRRTL SEQ ID No 232 DVDVDDTTEEQGYGMAYTVHKWSELSWASHWVTFGCW SEQ ID No 233 RYCWLRRQAALQRRLSAMEKGKLHKPGKDASKRGRQTP SEQ ID No 234 MKKAEMGRFSISPDEDSSSYSSNSDFNYSYPTKQAALK SEQ ID No 235 LKCLIVALPKIILAVKSKGKFYLVIEELSQLFRSLVPIQ SEQ ID No 236 ETLLNAPRAMGTSSSPPSPASVVAPGTTLFEESRLPVFT SEQ ID No 237 YVRSWRKAGPLPSQIPPTAPGGEQCPLYANVHHQKGKDEG SEQ ID No 238 TYLSEPLVRGYTTAAAVQVFVSQLKYVFGLHLSSHSGPLS SEQ ID No 239 RWWSQYTSIPLPDQLMCVISASVHGVDQRGRLLRRTL SEQ ID No 240 RRFRQACLETCARCCPRPPRARPRALPDEDPPTPSIASLSR SEQ ID No 241 MAEAITYADLRFVKAPLKKSISSRLGQDPGADDDGE SEQ ID No 242 MQTSEREGSGPELSPSVMPEAPLESPPFPTKSPAFDLFNLV SEQ ID No 243 SKEKQFRGLQSRIEQEQKFTVIRGGQVIQIPVADITVGDIAQ SEQ ID No 244 SKEKQFRGLQSRIEQEQKFTVVRAGQVVQIPVAEIVVGDIAQ SEQ ID No 245 SKEKQFRGLQCRIEQEQKFSIIRNGQLIQLPVAEIVVGDIAQ SEQ ID No 246 KCLQGNADGDGGGGQCCRRQDSPSPDFYKQSSPNLQVSSDGT SEQ ID No 247 SSECQRYVYSILCCKESSDPSSYNSSGQLMASKMDTCSSNLNN SEQ ID No 248 MDNQGVIYSDLNLPPNPKRQQRKPKGNKNSILATEQE SEQ ID No 249 WWGDIWWKTMMELRSLDTQKATCHLQQVTDLPWTSVSSPVERE SEQ ID No 250 RLLFSKTYKLQERSDLTVKEKEELIEEWQPEPLVPPVPKDHPA SEQ ID No 251 KYYPINMDFKPNFITTYKCECVAPDTVNTTVFNASAPLAPDTNA SEQ ID No 252 CIRRSCLHRRRTFTYQSGSGEETILQFSSGTLTLTRRPKLQPEP SEQ ID No 253 MTNPSDRVLPANSMAESREGDFGCTVMELRKLMELRSRDALTQIN SEQ ID No 254 WLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPS SEQ ID No 255 WCQCCPHTCCCYVRCPCCPDKCCCPEALYAAGKAATSGVPSIYAP SEQ ID No 256 AVCQCRRKNYGQLDIFPARDTYHPMSEYPTYHTHGRYVPPSSTDR SEQ ID No 257 TVVLRVQFPSWNGLGSIPSTDIYKSTKNYKNIEEPQGVKILRFSSP SEQ ID No 258 DNTVPGSPEERGLIQWKAGAHANSDMSSSLKSYDFPIGMGIVKRITF SEQ ID No 259 YRCSQHSSSSEESTKRTSHSKLPEQEAAEADLSNMERVSLSTADPQG SEQ ID No 260 GLKGIRSALKRPVEQPLGEIPEKSLHSIAVSSIQKAKGYQLLEEEKIV SEQ ID No 261 RWRRRKGQQRTKATTPAREPFQNTEEPYENIRNEGQNTDPKLNPKDDG SEQ ID No 262 RFTGHPGAYLRLINRWRLEECHPSGCLIDLCMQMGIIMVLKQTWNNFME SEQ ID No 263 VVALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENT SEQ ID No 264 SYRYVTKPPAPPNSLNVQRVLTFQPLRFIQEHVLIPVFDLSGPSSLAQP SEQ ID No 265 SNKCDVVVVGGGISGMAAAKLLHDSGLNVVVLEARDRVGGRTYTLRNQK SEQ ID No 266 TLRNATQQKDMVEVADFDFSPMSDKNPEPPSGVRCCCQMCCGPFLLE SEQ ID No 267 TP HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDR SEQ ID No 268 ETDTSALAAGSSQE MDEEEDGAGAEESGQPRSFMRLNDLSGAGGRPGPGSAEKDPGSADSE SEQ ID No 269 AEG EMLHLGFGTIRDSLNSKRRELEDPGAYNYPFTWNTPSAPPGYNIAVKPDQ SEQ ID No 270 AKTGRTSIQRDLKEQQPQALAPGRGPSHSSAFSMSPLSTAQAPLPNPRT SEQ ID No 271 AA LCLRKQSNGREAEYSDKHGQYLIGHGTKVYIDPFTYEDPNEAVREFAKEID SEQ ID No 272 KNFRRDFFILLSKCGCYEMQAQIYRTETSSTVHNTHPRNGHCSSAPRVT SEQ ID No 273 NG QDIGYFLKVAAVGRRVRSYGKRRPARTILRAFLEKARQTPHKPFLLFRDET SEQ ID No 274 MSAARPQFSIDDAFELSLEDGGPGPESSGVARFGPLHFERRARFEVAD SEQ ID No 275 EDKQSR YAATSRQLKRLESVSRSPIYSHFSETVTGASVIRAYNRSRDFEIISDTKVD SEQ ID No 276 ANQR MTVPKEMPEKWARAQAPPSWSRKKPSWGTEEERRARANDREYNEKF SEQ ID No 277 QYASNCIKT KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAP SEQ ID No 278 TVEMDEE KARRKQAAGRPEKMDDEDPIMGTITSGSRKKPWPDSPGDQASPPGDA SEQ ID No 279 PPLEEQKE RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAG SEQ ID No 280 PISEDEQE MKFEEKCGDNGSIVGRNQSYPGEKHQPKGKPIANGEAEVYAKQEANGK SEQ ID No 281 CSTPRKSL DIKINQYIIKKCSPCCACLAKAMERSEQQPLMGWEDEGQPFIRRQSRTD SEQ ID No 282 SGIFYED MAEPQAESEPLLGGARGGGGDWPAGLTTYRSIQVGPGAAARWDLCID SEQ ID No 283 QAVVFIEDA AVTISLAYSVKKMMKDNNLVRHLDACETMGNATAICSDKTGTLTTNRMT SEQ ID No 284 VVQAYVGD AVTISLAYSVKKMMKDNNLVRHLDACETMGNATAICSDKTGTLTMNRMT SEQ ID No 285 VVQAYIGG SNMKSRSAGKLWELQHEIEVYRKTVIAQWRALDLDVVLTPMLAPALDLN SEQ ID No 286 APGRATGA HPELNVQKRKRSFKAVVTAATMSSRLSHKPSDRPNGEAKTELCENVDP SEQ ID No 287 NSPAAKKKY RKSNFIFDKLHKVGIKTRRQWRRSQFCDINILAMFCNENRDHIKSLNRLD SEQ ID No 288 FITNESD KICRKEARKRAAAEQDVPSTLGPISQGHQHECSAGSSQDHPPPGAATY SEQ ID No 289 TPGKGEEQE SGKTLESWRSLCTRCCWASKGAAVGGGAGATAAGGGGGPGGGGGG SEQ ID No 290 GPGGGGGPGGGGG RSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGL SEQ ID No 291 AAHSSGEERE MKSKMRQALGFAKEARESPDTQALLTCAEKEEENQENLDWVPLTTLSH SEQ ID No 292 CKSLRTMTAI AILFAVVARGTTILAKHAWCGGNFLEVTEQILAKIPSENNKLTYSHGNYLF SEQ ID No 293 HYICQDR MDHAEENEILAATQRYYVERPIFSHPVLQERLHTKDKVPDSIADKLKQAF SEQ ID No 294 TCTPKKIRN KKLVKKFRQKKQRQWIGPTGMNQNMSFHRNHTATVRSHAENPTASHV SEQ ID No 295 DNEYSQPPRNSHL MPRRLQPRGAGTKGPPAPAPAASGAARNSHSAASRDPPASAKPLLRW SEQ ID No 296 DEVPDDFVECFIL RSCRKKSARPAVGVGDTGMEDANAVRGSASQGPLIESPADDSPPHHAP SEQ ID No 297 PALATPSPEEGE DNFEYLTRDSSILGPHHLDEFIRVWAEYDPAACGRISYNDMFEMLKHMS SEQ ID No 298 PPLGLGKKCPAR SKRWTHLPCGCIINCRQNAYAVASDGKKIKRKGFEFNLSFQKSYGIYKIA SEQ ID No 299 HEDYYDDDENS NFNYFYHRETEGEEQSQYMHVGSCQHLSSSAEELRKARSNSTLSK SEQ ID No 300 VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQP SEQ ID No 301 PPASARSSVGEGE LKLANEETIKNITHWTLFNYYNSSGWNESVPRPPLHPADVPRGSCWETA SEQ ID No 302 VGIEFMRLTVSDML MCHSRSCHPTMTILQAPTPAPSTIPGPRRGSGPEIFTFDPLPEPAAAPAG SEQ ID No 303 RPSASRGHRKRSRR ASSAASSEHFEKLHEIFRGLHEDLQGVPERLLGTAGTEEKKKLIRDFDEK SEQ ID No 304 QQEANETLAEMEEE MADQIPLYPVRSAAAAAANRKRAAYYSAAGPRPGADRHSRYQLEDESA SEQ ID No 305 HLDEMPLMMSEEGFENEE SMILSASVIRVRDGLPLSASTDYEQSTGMQECRKYFKMLSRKLAQLPDR SEQ ID No 306 CTLKTGHYNINFISSLG LTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGL SEQ ID No 307 CGEQRGEDCAELHDYFNV TIPTSRLKFLKEAGRLTQKEEIPEEELNEDVEEIDHAERELRRGQILWFRG SEQ ID No 308 LNRIQTQIRVVKAFRS TIPTSQLKCLKEAGHGPGKDEMTDEELAEGEEEIDHAERELRRGQILWF SEQ ID No 309 RGLNRIQTQIRVVKAFRS KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHND SEQ ID No 310 DVRNHAMKPINDNKEPLNSD MGDTHWRVAQERDELWRAQVVATTVMLERKLPRCLWPRSGICGCEFG SEQ ID No 311 LGDRWFLRVENHNDQNPLRV YSPGDYICKKGDIGREMYIIKEGKLAVVADDGVTQFVVLSDGSYFGEISIL SEQ ID No 312 NIKGSKAGNRRTANIKS FSPGDYICRKGDIGKEMYIIKEGKLAVVADDGVTQYALLSAGSCFGEISIL SEQ ID No 313 NIKGSKMGNRRTANIRS CLKIIKEYERAVVFRLGRIQADKAKGPGLILVLPCIDVFVKVDLRTVTCNIP SEQ ID No 314 PQEILTRDSVTTQVDG MTEGARAADEVRVPLGAPPPGPAALVGASPESPGAPGREAERGSELGV SEQ ID No 315 SPSESPAAERGAELGADEEQR VRLRLQKHRPPADPCRGETETMNNLANCQREKDISVSIIGATQIKNTNKK SEQ ID No 316 ADFHGDHSADKNGFKARYPA VITTCLALGTRRMAKKNAIVRSLPSVETLGCTSVICSDKTGTLTTNQMSV SEQ ID No 317 CRMFILDRVEGDTCSLNEFTITG MEAVLNELVSVEDLLKFEKKFQSEKAAGSVSKSTQFEYAWCLVRSKYND SEQ ID No 318 DIRKGIVLLEELLPKGSKEEQRDY TRPKPLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYE SEQ ID No 319 GFQRGIQVSNNGPCLGSRKPDQPYEW HRPKALQPPCNLLMQSEEVEDSGGARRSVIGSGPQLLTHYYDDARTMY SEQ ID No 320 QVFRRGLSISGNGPCLGFRKPKQPYQW RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYD SEQ ID No 321 NDPDLCFRMQEGSEVYSNPCLEENKPG WSCERYRADVRTVWEQCVAIMSEEDGDDDGGCDDYAEGRVCKVRFD SEQ ID No 322 ANGATGPGSRDPAQVKLLPGRHMLFPPLER GPLVRYLDVKKTNKKESINEELHIRLMDHLKAGIEDVCGHWSHYQVRDK SEQ ID No 323 FKKFDHRYLRKILIRKNLPKSSIV KYPTLLHQRKKQRFLSKHISHRGGAGENLENTMAAFQHAVKIGTDMLEL SEQ ID No 324 DCHITKDEQVVVSHDENLKRATGVNVNISD AHDHYTVDVVVAYYITTRLFWWYHTMANQQVLKEASQMNLLARVWWY SEQ ID No 325 RPFQYFEKNVQGIVPRSYHWPFPWPVVHLSRQ SKASRAPRAHRDINVPRALVDILRHQAGPGTRPDRARSSSLTPGIGGPD SEQ ID No 326 SMPPRTPKNLYNTVKTPNLDWRALPPPSPS FKVYKWKQSRDLYRAPVSSLYRTPGPSLHADAVRGGLMSPHLYHQVYL SEQ ID No 327 TTDSRRSDPLLKKPGAASPLASRQNTLRSCDP MLCRKTSQQEHVYEAARAHAREANDSGETMRVAIFASGCSSDEPTSQN SEQ ID No 328 LGNNYSDEPCIGQEYQIIAQINGNYARLLDTVP KQKNEHHHGHSHYASESLPSKKDQEEGVMEKLQNGDLDHMIPQHCSS SEQ ID No 329 ELDGKAPMVDEKVIVGSLSVQDLQASQSACYWLKG HKALMERALRATFREALSSLHSRRRLDTEKKHQEHLLLSILPAYLAREMK SEQ ID No 330 AEIMARLQAGQGSRPESTNNFHSLYVKRHQGVS HKHQMQDASRDLFTYTVKCIQIRRKLRIEKRQQENLLLSVLPAHISMGMK SEQ ID No 331 LAIIERLKEHGDRRCMPDNNFHSLYVKRHQNVS ERFVAKPCAIALNIQANGPQIAPPNAILEKVFTAITKHPDEKRLEGLSKQLD SEQ ID No 332 WDVRSIQRWFRQRRNQEKPSTLTRFCESMWRF AWRLWRCRVARSRELNKPWAAQDGPKPGLGLQPRYGSRSAPKPQVA SEQ ID No 333 VPSCPSTPDYENMFVGQPAAEHQWDEQGAHPSEDNDFY HLSQWTRGRSRSHPGQGRSGESVEEVPLYGNLHYLQTGRLSQDPEPD SEQ ID No 334 QQDPTLGGPARAAEEVMCYTSLQLRPPQGRIPGPGTP KKRHCGYSKAFQDSDEEKMHYQNGQAPPPVFLPLHHPPGKLPEPQFYA SEQ ID No 335 EPHTYEEPGRAGRSFTREIEASRIHIEKIIGSGDSGE QSVFNKRKSRVRHYLVKCPQNSSGETVTSVTSLAPLQPKKGKRQKEKP SEQ ID No 336 DIPPAVPAKAPIAPTFHKPKLLKPQRKVTLPKIAEEN MASPGAGRAPPELPERNCGYREVEYWDQRYQGAADSAPYDWFGDFS SEQ ID No 337 SFRALLEPELRPEDRILVLGCGNSALSYELFLGGFPNVTS MPHFTVVPVDGPRRGDYDNLEGLSWVDYGERAELDDSDGHGNHRESS SEQ ID No 338 PFLSPLEASRGIDYYDRNLALFEEELDIRPKVSSLLGKL AIPTRSLKFLKEAGHGTTKEEITKDAEGLDEIDHAEMELRRGQILWFRGL SEQ ID No 339 NRIQTQIDVINTFQTGASFKGVLRRQNMGQHLDVKLVPS IFMKTAQAHRRAETLIFSKHAVIALRHGRLCFMLRVGDLRKSMIISATIHM SEQ ID No 340 QVVRKTTSPEGEVVPLHQVDIPMENGVGGNSIFLVAPL SWKRYPASMKQLQQRSLMRRHRKKKRQSLKQMTPSTQEFYVDYKPTN SEQ ID No 341 TETSEMLLNGTGPCTYNKSGSRECEIPLSMNVSTFLAYDQPT MANVSKKVSWSGRDRDDEEAAPLLRRTARPGGGTPLLNGAGPGAARQ SEQ ID No 342 SPRSALFRVGHMSSVELDDELLDPDMDPPHPFPKEIPHNEKLLS RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYD SEQ ID No 343 EILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGT AMCLWKNRQQNTIQKYDPPGYLYQGSDMNGQMVDYTTLSGASQINGN SEQ ID No 344 VHGGFLTNGGLS LGSGFALKVQEQHRQKHFEKRRMPAANLIQAAWRLYSTDMSRAYLTAT SEQ ID No 345 WYYYDSILPSFRELALLFEHVQRARNGGLRPLEVRRAPVPDGAP MSSHKGSVVAQGNGAPASNREADTVELAELGPLLEEKGKRVIANPPKAE SEQ ID No 346 EEQTCPVPQEEEEEVRVLTLPLQAHHAMEKMEEFVYKVWEGRWRV WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLS SEQ ID No 347 SAQVDQVEVEYVTMASLPKED HYARARRKPGGLSATGTSSHSPSECQEPSSSRPSRIDPQEPTHSKPLAP SEQ ID No 348 MELEPMYSNVNPGDSNPIYSQIWSIQHTKENSANCPMMHQEHEELT MAKRKQGNRLGVCGRFLSSRVSGMNPSSVVHHVSDSGPAAELPLDVP SEQ ID No 349 HIRLDSPPSFDNTTYTSLPLDSPSGKPSLPAPSSLPPLPPKVLVCSKP SPNRKNPLWPSVPDPAHSSLGSWVPTIMEEDAFQLPGLGTPPITKLTVL SEQ ID No 350 EEDEKKPVPWESHNSSETCGLPTLVQTYVLQGDPRAVSTQPQSQSGTS DQ KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK SEQ ID No 351 LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTY

TABLE 4 Examples of naturally occurring C-terminal flanking regions of ITIM only intracellular domains (Table 4 comprises SEQ ID No 352 to SEQ ID No 685) K I N R E S R G Q I A YA VQ QE MT SK AR AK RR QI QI LT VI VLT KVS ARS IFR TFL QGVQ SEQ ID No 352 FSVR SEQ ID No 353 YSSK SEQ ID No 354 PKTR SEQ ID No 355 VNDT SEQ ID No 356 GMQQ SEQ ID No 357 PDLL SEQ ID No 358 HKSL SEQ ID No 359 RQPLN SEQ ID No 360 RTPTN SEQ ID No 361 RNLTN SEQ ID No 362 TVFSP SEQ ID No 363 NRFMK SEQ ID No 364 LNAIA SEQ ID No 365 LFTML SEQ ID No 366 MYVMG SEQ ID No 367 VTGTR SEQ ID No 368 TTHRR SEQ ID No 369 VTRRK SEQ ID No 370 VTPVR SEQ ID No 371 MTVRK SEQ ID No 372 MTVKR SEQ ID No 373 VTPRR SEQ ID No 374 KPWWD SEQ ID No 375 NRLMK SEQ ID No 376 FKETV SEQ ID No 377 PFLKNT SEQ ID No 378 VTQRRG SEQ ID No 379 MTERKA SEQ ID No 380 VTMRRT SEQ ID No 381 RQALAE SEQ ID No 382 APDSNT SEQ ID No 383 SKKRGG SEQ ID No 384 EISAAS SEQ ID No 385 STLGPG SEQ ID No 386 NSLSFL SEQ ID No 387 AHLVQY SEQ ID No 388 DEHDAII SEQ ID No 389 VTKRCAR SEQ ID No 390 KRIEHAK SEQ ID No 391 VTPWRLR SEQ ID No 392 VTPCRLR SEQ ID No 393 RWGFSKQ SEQ ID No 394 RGDDKDC SEQ ID No 395 ATRMMMG SEQ ID No 396 GPSRDPD SEQ ID No 397 VTLPRARR SEQ ID No 398 RLPYQLAQ SEQ ID No 399 LGSFLIGS SEQ ID No 400 MGDDSSNS SEQ ID No 401 PLSHLAQN SEQ ID No 402 ATEGKSVC SEQ ID No 403 HNNCEKDSV SEQ ID No 404 RTMKPLPRH SEQ ID No 405 SQRRNPWQA SEQ ID No 406 YPMKITGNR SEQ ID No 407 VSHLRSPRK SEQ ID No 408 SYPARTRKV SEQ ID No 409 WGRLRFARK SEQ ID No 410 VFLNKVMRG SEQ ID No 411 SGSGYQLV SEQ ID No 412 HSDSLGSAS SEQ ID No 413 KATVHLAYL SEQ ID No 414 CAEDYHWQWR SEQ ID No 415 QRLLVKAKTQ SEQ ID No 416 EDFLEESRNQ SEQ ID No 417 GEKAFGWPGK SEQ ID No 418 PTVSPFLRQR SEQ ID No 419 PRTVLWLTIE SEQ ID No 420 EVCWKLPQSK SEQ ID No 421 ISNRWLSIGV SEQ ID No 422 GNCSFFTETG SEQ ID No 423 DSIRGYFGET SEQ ID No 424 LHSNSFIRNNY SEQ ID No 425 TYYSETTVTRT SEQ ID No 426 TYYSRRTLLGV SEQ ID No 427 SSYFLGKLLSD SEQ ID No 428 QARLRQHYQTI SEQ ID No 429 LVFHHMAQHLMM SEQ ID No 430 YSTKITIPVIKR SEQ ID No 431 TYHSERTVTFTY SEQ ID No 432 PGSNYSEGWHIS SEQ ID No 433 LCANKKSSVKIT SEQ ID No 434 DGSPDYQKAKLQ SEQ ID No 435 VRRQLPVEEPNP SEQ ID No 436 KLNQVVRKVSAL SEQ ID No 437 ILRDYKQSSSTL SEQ ID No 438 DPAKYARWKPWLK SEQ ID No 439 QLRFNKPVRYAAT SEQ ID No 440 ELRFNKCVRLCGT SEQ ID No 441 GLKDQVNTVGIPI SEQ ID No 442 YKTSQNALDFNTKV SEQ ID No 443 PSENKENSAVPVEE SEQ ID No 444 ARTKISDDDDEHTL SEQ ID No 445 PITKWLPAYKFKEY SEQ ID No 446 SNLDEVGQQVERLD SEQ ID No 447 RATASLNANEVEWF SEQ ID No 448 EMRFSRAVRLCGTLQ SEQ ID No 449 RICSLTASEGPQQKI SEQ ID No 450 PLSPYGDIIEK SEQ ID No 451 TSESKENCTGVQVAE SEQ ID No 452 SQMNPRSPPATMCSP SEQ ID No 453 MHPDALEEPDDQNRI SEQ ID No 454 LSRMQHQSQECKSEE SEQ ID No 455 QEPNESDLPYHEMETL SEQ ID No 456 SRENSSSQDPQTEGTR SEQ ID No 457 EPSGHEKEGFMEAEQC SEQ ID No 458 KGSNYHLSDNDASDVE SEQ ID No 459 HTQSAEPPPPPEPARI SEQ ID No 460 CLISEERNECVIATEV SEQ ID No 461 ASWATNLKSSIRKANK SEQ ID No 462 TSMQPTEAMGEEPSRAE SEQ ID No 463 LSQEHRLLRHSSMADKK SEQ ID No 464 YSQKPPKRASSQLSWFS SEQ ID No 465 PRRPGEPREVHIGRALGR SEQ ID No 466 DTLSTRPGYLWVVWIYRN SEQ ID No 467 SIMNADILNYCQKESWCK SEQ ID No 468 NRGPPLDRAEVYSSKLQD SEQ ID No 469 ISKLSHSKGHQKRKALKTT SEQ ID No 470 DQNVNEAMPSLKITNDYIF SEQ ID No 471 DNSPLRRKSIYLVIIV SEQ ID No 472 QGQRSDVYSDLNTQRPYYK SEQ ID No 473 EIYLEPLKDAGDGVRYLLR SEQ ID No 474 LKHDTNIYCRMDHKAEVAS SEQ ID No 475 QWPALKEKYPKSVYLGRIV SEQ ID No 476 GKIFSSCFHNTILCMQKESE SEQ ID No 477 LDDHDYGSWGNYNNPLYDDS SEQ ID No 478 VRENHGLLPPLYKSVKTYTV SEQ ID No 479 PCTAQECLASVLKPTNETLN SEQ ID No 480 PNCNKPRWEKWFMVTFASST SEQ ID No 481 GYKAFGLVGKLAASGSITMQN SEQ ID No 482 FGRTVAIKPPKCWTGRFLMNL SEQ ID No 483 FRRTVSSKTPKCPTGRLLMNL SEQ ID No 484 NFHGMNPSKDTSTEYSEVRTQ SEQ ID No 485 HNPTLQVFRKTALLGANGAQP SEQ ID No 486 GELSLASLHIPFVETQHQTQV SEQ ID No 487 GEEGVALPANGAGGPGGASARK SEQ ID No 488 DRRSNQVARALHDHLGLRQGDC SEQ ID No 489 NHRVDASSMWLYRRYYSNVCQR SEQ ID No 490 QKMDSLDAMEGDVELEWEETTM SEQ ID No 491 FHTLRGKGQAAEPPDFNPRDSYS SEQ ID No 492 SVYQYGSALAHFFYSSDQAWYDR SEQ ID No 493 DSAEAPADPFAVPEGRSQDARGY SEQ ID No 494 SAGNGGSSLSYTNPAVAATSANL SEQ ID No 495 KAKLQSSPDYLQVLEEQTALNKI SEQ ID No 496 LLKGLGRRQACGYCVFWLLNPLPM SEQ ID No 497 SRGLQGTYQDVGSLNIGDVQLEKP SEQ ID No 498 APVVFFYLSQDSRPRSWCLRTVCN SEQ ID No 499 HFHKVQPQEPKVTDTEYSEIKIHK SEQ ID No 500 SISLHGLSQVSEDPPSVFNMPEAD SEQ ID No 501 VNNCEHFVTLLRYGEGVSEQANRA SEQ ID No 502 QNWGPRFKKLADLYGSKDTFDDDS SEQ ID No 503 KLRSDCSRPSLQWYTRAQSKMRRPS SEQ ID No 504 DHSRSTKAVSEKKAKGLGESRKDKK SEQ ID No 505 STGLTWRSGTASSVSYPKQMPLSQV SEQ ID No 506 AATVFFCLGQTTRPRSWCLRLVCNP SEQ ID No 507 YAANPVITPEPVTSPPSYSSEIQANK SEQ ID No 508 NHCVFTQRKITRPSQRPKTPPTDTSV SEQ ID No 509 TQGAKEHEEAESGEGTRRRAAEAPSM SEQ ID No 510 DHLALSRPRRLSTADPADASTIYAVVV SEQ ID No 511 STSALSEAASDTTQEPPGSHEYAALKV SEQ ID No 512 SFHKGEPQDLSGQEATNNEYSEIKIPK SEQ ID No 513 EGALHRSSMQPDNSSDSDYDLHGAQRL SEQ ID No 514 SFHKARPQYPQEQEAIGYEYSEINIPK SEQ ID No 515 SFQMVKPWDSRGQEATDTEYSEIKIHR SEQ ID No 516 IFPGGNKGGGTSCGPAQNPPNNQTPSS SEQ ID No 517 ELPTATQAQNDYGPQQKSSSSRPSCSCL SEQ ID No 518 KVPAEEPANELPMNEIEAWKAAEKKARW SEQ ID No 519 SHQWKSSEDNSKTFSASHNVEATSMFQL SEQ ID No 520 KEEEMADTSYGTVKAENIIMMETAQTSL SEQ ID No 521 NLTALDWSLLSKKECLSYGGRLLGNSCK SEQ ID No 522 SFSEMKSREPKDQEAPSTTEYSEIKTSK SEQ ID No 523 ELIKPHRAAKGAPTSTVYAQILFEENKL SEQ ID No 524 NHSVIGPNSRLARNVKEAPTEYASICVRS SEQ ID No 525 DLASQPVYCNLQSLGQAPMDEEEYVIPGH SEQ ID No 526 DYDNSENQLFLEEERRINHTAFRTVEIKR SEQ ID No 527 DHSGGHHSDKINKSESVVYADIRKN SEQ ID No 528 DHWALTQRTARAVSPQSTKPMAESITYAAVARH SEQ ID No 529 ENLIYENVAAIQAHKLEV SEQ ID No 530 SETTGLTPDQVKRNLEKYGLNELPAEEGKT SEQ ID No 531 SLCYKFLSYFRASSTMRY SEQ ID No 532 KLEKLVSSLREEDEYSIHPPSSRWKRFYRA SEQ ID No 533 SHLRKIRTCTSIMEKDLTYSSVKRHL SEQ ID No 534 ALSSSTSPRAPPSHRPLKSPQNETLYSVLKA SEQ ID No 535 DPENQNFLLESNLGKKKYETEFHPGTTSFGMS SEQ ID No 536 FTYGVRFLKKTPWLWNTRHCWYNYPYQPLTTD SEQ ID No 537 KTLRSLEATDSAFDNPDYWHSRLFPKANAQRT SEQ ID No 538 QFQNSSEMEKIPEIGKFGEKAPPAPSHVWRPAA SEQ ID No 539 TFQDSAGARNNRDGNNLRKRGHPAPSPIWRHAA SEQ ID No 540 LALSSGSRKASAVGDVVNLVSVDVQRLTESVLY SEQ ID No 541 DILRPYFDVEPAQVRSRLLESMIPIKMVNFPQK SEQ ID No 542 TCQFEGLLRPYIQHAMYDEEKGTPIFICPVSWG SEQ ID No 543 LQLDKVDVIPVTAINLYPDGPEKRAENLEDKTCI SEQ ID No 544 CPVFKGFSSSSKDQIAIPEDTPENTETASVCTKV SEQ ID No 545 NFEAQQPTQPTSASPSLTATEIIYSEVKKQ SEQ ID No 546 WSMQQPESSANIRTLLENKDSQVIYSSVKKS SEQ ID No 547 GRQPGKREPLRSVLRRALGEGAELGARGQSLPMGLL SEQ ID No 548 PDWLKDNDYLLHGHRPPMPSFRACFKSIFRIHTETG SEQ ID No 549 DGSHIHTFLDVSFSEALYPVFRILTLEPTALTICPA SEQ ID No 550 DHWALTQRTARAVSPQSTKPMAESITYAAVARH SEQ ID No 551 HSLTLRREATEPPPSQEREPPAEPSIYAPLAIH SEQ ID No 552 RFKNEFKSSGINTASSAASKERTAPHKSNTGFPKLLCA SEQ ID No 553 REKMWHGRQRLGGVGAGSRPPMPAHPTPASIFSARSTDV SEQ ID No 554 KKTHPDDSAGEASSRGRAHEEDDEENYENVPRVLLASDH SEQ ID No 555 GSAQGRRLPLRLVLQRALGDEAELGAVRETSRRGLVDIAA SEQ ID No 556 SSPTSPTSPGPQQAPPRETYLSEKIPIPDTKPGTFSLRKL SEQ ID No 557 AGFPKTRLGRLATSTSRSRQLSLCDDYEEQTDEYFFDRDP SEQ ID No 558 KSLMARRTYLEWPKEKSKRGLFWANLRAAINIKLTEQAKK SEQ ID No 559 LPWEPSLESEEEVEEEETSEALVLNPRRHQDSSRNKAGGLP SEQ ID No 560 KESDHFSTELDDITVTDTYLSATKVSFDDTCLASEVSFSQS SEQ ID No 561 QNLCSRLKTSPVEGLSGNPADLEKRRQVFGHNVIPPKKPKT SEQ ID No 562 NHCVFTQRKITRPSQRPKTPPTDIIVYTELPNAEP SEQ ID No 563 TMKTSDKFKFVFREKMGRIVDYFTIQNPSNVDH SEQ ID No 564 SENFRKAYKQVFKCHIRKDSHLSDTKESKSRIDTPPSTNCTHV SEQ ID No 565 EFMNEQKLNRYPASSLVVVRSKTEDHEEAGPLPTKVNLAHSEI SEQ ID No 566 GNYRLKEYEKALKYVRGLLQTEPQNNQAKELERLIDKAMKKDG SEQ ID No 567 PAGEEDEEEEEDLGWGCPDVAGPTRPTAPPDLHNYMRRIKEIA SEQ ID No 568 SGLREQTIAIKCLVVLVVALGLPFLAIGYWIAPCSRLGKILRS SEQ ID No 569 SGLRQQTMAVKFLVVLAVAIGLPFLALIYWFAPCSKMGKIMRG SEQ ID No 570 SGLRQQTMAVKFLVVLAVAIGLPFLALIYWFAPCSKMGKIMRG SEQ ID No 571 PPVSRAYTTACVLTTAAVQLELITPFQLYFNPELIFKHFQIWRL SEQ ID No 572 GNVLILRSVSTAVYKRFPSAQHLVQAGFMTPAEHKQLEKLSLPH SEQ ID No 573 QNWWTRRKVRQEHGPERKISFPQWEKDYNLQPMNAYGLFDEYLE SEQ ID No 574 DSNIAFSVNASDKGEASCCDPVSAAFEGCLRRLFTRWGSFCVRNP SEQ ID No 575 QVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT SEQ ID No 576 VLDSEPKSQASGPEPELYASVCAQTRRARASFPDQAYANSQPAAS SEQ ID No 577 ETGINLRGALLAMIYNKILRLSTSNLSMGEMTLGQINNLVAIETNQ SEQ ID No 578 AAGRARAKACRAPGSYGRGTHCHYKAPTVVLHMTKTDPSLENPTHL SEQ ID No 579 HHELLSHKSFETNAQEDTMETHLETELDLSTITTAGRISDHKQQLA SEQ ID No 580 DQKYVLILNVFPAPPKRSFLPQVLTEWYIPLEKDERHQWIVLLSFQL SEQ ID No 581 LQTVYLGKNSEAQPARQILVLDNAAIVCNFGSELSLVYVPSVLEKLD SEQ ID No 582 RKDSEEEVSLLGSQDIEEGNHQVEDGCREMACEEFNFGEILMTQVIHS SEQ ID No 583 QRRETEVYACIENEDGSSPTAKQSPLSQERPHRFEDDGELNLVYENL SEQ ID No 584 APCAKVRPYIAEGESDTDSDLCTPCGPPPRSATGEGPFGDVGWAGPRK SEQ ID No 585 ERLGYSEDGLEELSRHSVSEADRLLSARSSVDFQAFGVKGGRRINEYFC SEQ ID No 586 RQRLCRQSVLLWPHQPSGQRSFWAQLGMALTRDNHHFYNRNFCQGP SEQ ID No 587 TAE LHRDYDRTVTLLSPPRPGRLPDLQEIGVPLYQSPPGRYLSPKKGANENV SEQ ID No 588 RSPFYDRFSEARILFLLQLLADHVPGVGLVTRPLMDYLPTWQKIYFYSWG SEQ ID No 589 NPSPDTRIELNDVVYLIRPDPLAYLPNSEPSRRNSICNVTGQDSREETQL SEQ ID No 590 RDIYAQRMHTFITSLSSVGIVVSDPDSTDASSIEDNEDICNTTSLENCTAK SEQ ID No 591 SFQGLRLWEPADQEAPSTTEYSEIKIHTGQPLRGPGFGLQLEREMSGM SEQ ID No 592 VPK LVSSVADVLAQGGGPRSSQHCGEGSQLVAADHRGGLDGWEQPGAGQ SEQ ID No 593 PPSDT VVSDSGISTDYSSGDSQGAQGGLSDGPYSNPYENSLIPAAEPLPPSYVA SEQ ID No 594 CS NPPPDTRLEPSDIVYLIRSDPLAHVASSSQSRKSSCSHKLSSCNPETRDE SEQ ID No 595 TQL HPSCCWKPDPDQVDGARSLLSPEGYQLPQNRRMTHLAQKFFPKAKDE SEQ ID No 596 AASPVKG GKKFKRYFLQLLKYIPPKAKSHSNLSTKMSTLSYRPSDNVSSSTKKPAPC SEQ ID No 597 FEVE SDNFKKSFQNVLCLVKVSGTDDGERSDSKQDKSRLNETTETQRTLLNG SEQ ID No 598 DLQTSI SPTNNTVYASVTHSNRETEIWTPRENDTITIYSTINHSKESKPTFSRATAL SEQ ID No 599 DNV LGGAAYVNTFHNIALETSDEHREFAMAATCISDTLGISLSGLLALPLHDFL SEQ ID No 600 CQLS MQKDSSQETTSCYEKIFYGHLLKKFRQPNFARKLC SEQ ID No 601 ALATSKALVKFDPEIIGPRDIIKIIEEIGFHASLAQRNPNAHHLDHKMEIKQ SEQ ID No 602 WKKS NHCVFTQRKITRPSQRPKTPPTDIIVYTELPNAESRSKVVSCP SEQ ID No 603 DHCVFTQRKITRPSQRPKTPPTDTILYTELPNAKPRSKVVSCP SEQ ID No 604 ERKRIQYLHAKLLKKRSKQPLGEVKRRLSLYLTKIHFWLPVLKMIRKKQM SEQ ID No 605 DMASADKS SEWLESIRMKRYILHFHSAGLDTMECVLELTAEDLTQMGITLPGHQKRIL SEQ ID No 606 CSIQGFKD NADAKYPGYPPEHIIAEKRRARRRLLHKDGSCNVYFKHIFGEWGSYVVDI SEQ ID No 607 FTTLVDTKW HRTSKRSEARSAEFTVGRKDSSIICAEVRCLQPSEVSSTEVNMRSRTLQ SEQ ID No 608 EPLSDCEEVLC IKYWFHTPPSIPLQIEEYLKDPTQPILEALDKDSSPKDDVWDSVSIISFPEK SEQ ID No 609 EQEDVLQTL RREPRQALAGTFRDLRLRLWPQGGGWVQQVALKQVGRRWVASNPRE SEQ ID No 610 SRPSTLLTNLDRGTPG DFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSA SEQ ID No 611 QPLRPEDGHCSWPL ENDEDGAQASPEPDGGVGTRDSSRTSIRSSQWSFSTISSSTQRSYNTC SEQ ID No 612 CSWTQHPLIQKNRR DEIYLESCCQARYHQKKEQMNEELKREAETLREREGEEFDNTCCAEKR SEQ ID No 613 KKLWDLLEKPNSSV DMRPPPTAMITLNNSVYWQEFEDTCVYECLDGKDCQSFFCCYEECKSG SEQ ID No 614 SWRKGRIHIDILELDS GTLAWMITLSDGLHNFIDGLAIGASFTVSVFQGISTSVAILCEEFPHELGD SEQ ID No 615 FVILLNAGMSIQQ GHNEVIGVCRVGPDAADPHGREHWAEMLANPRKPVEHWHQLVEEKTV SEQ ID No 616 TSFTKGSKGLSEKENSE PSLSTSNKNIYEVEPTVSVVQEGCGHNSSYIQNAYDLPRNSHIPGHYDLL SEQ ID No 617 PVRQSPANGPSQDKQS DEARLERCCLRRLRRREEEAAEARAGPTERGAQGSPARALGPRGRLQ SEQ ID No 618 RGRRRLRDVVDNPHSGLAGK DELSIDSCCRDRYFRRKELSETLDFKKDTEDQESQHESEQDFSQGPCPT SEQ ID No 619 VRQKLWNILEKPGSSTAAR KETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRR SEQ ID No 620 SSSDEQGLSYSSLKNV LSYNHHRLEEHEAETYEDGFTGNPSSLSQIPETNSEETTVIFEQLHSFVV SEQ ID No 621 DDDGFIEDKYIDIHELCEEN DESSSSPGRQMSSSDGGPPGQSDTDSSVEESDFDTMPDIESDKNIIRTK SEQ ID No 622 MFLYLSDLSRKDRRIVSKKYK RIIQEKKKHAVASDPRHLRNKGSPIIYSEVKVASTPVSGSLFLASSAPHR SEQ ID No 623 AEDHLDGCCKRRYLQKIEEFAEMVEREEEDDALDSEGRDSEGPAEGEG SEQ ID No 624 RLGRCMRRLRDMVERPHSGLPGK EDPWIGSESDKFILLGYLDQLRKDPALLSSEAVLPDLTDELAPVFLLRWF SEQ ID No 625 YSASDYISDCWDSIFHNNWRE MDRKWYFLCNSWLSINVGDCVLDKVFPVATEQDRKQFSHLFFMKTSAG SEQ ID No 626 FQDGHIWYSIFSRCARSSFTRVQR VPSDPSVEEMRKVVCEQKLRPNIPNRWQSCEALRVMAKIMRECWYAN SEQ ID No 627 GAARLTALRIKKTLSQLSQQEGIKM CSDFQEDIVFPFSLGWSSLVHRFLGPRNAQRVLLGLSEPIFQLPRSLAST SEQ ID No 628 PTAPTTPATPDNASQEELMITL RIPLLGDEEEGSEDEGESTHLLPENENELEKFIHSVIISKRSKNIKKKLKEE SEQ ID No 629 QNSVTENKTKNASHNGKMEDL SKIPQITLNFVDLKGDPFLASPTSDREIIAPKIKERTHNVTEKVTQVLSLGA SEQ ID No 630 DVLPEYKLQAPRIHRWTILHY DHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALM SEQ ID No 631 GSSRETTALSQTQLASSNVPAAGI PRARIMQRKRGLEWFVCDGWKFLCTSCCGWLINICRRKKELKARTVWL SEQ ID No 632 GCPEKCEEKHPRNSIKNQKYNVFTFI SPRHYYSGYSSSPEYSSESTHKIWERFRPYKKHHREEVYMAAGHALRK SEQ ID No 633 KVQFAKDEDLHDILDYWKGVSAQQKL SPQYHSLSYSSSPEYTCRASQSIWERFRLSRRRHKEEEEFMAAGHALR SEQ ID No 634 KKVQFAKDEDLHDILDYWKGVSAQHKS MAFNAKVSDPLIGGTYMTLLNTVSNLGGNWPSTVALWLVDPLTVKECVG SEQ ID No 635 ASNQNCRTPDAVELCKKLGGSCVTALD YYPHGHSHSLGLDLNLGLGSGTFHSLGNALVHGGELEMGHGGTHGFG SEQ ID No 636 YGVGHGLSHIHGDGYGVNHGGHYGHGGGH SFHKVKPQDPQGQEATDSEYSEIKIHKRETAETQACLRNHNPSSKEVRG SEQ ID No 637 NNSTSANRNVYEVEPTVSVVQGVFSNNGRLSQDPYDLPKNSHIPCHYD SEQ ID No 638 LLPVRDSSSSPKQEDSGGSSSNSSSSSE RREFRKALKSLLWRIASPSITSMRPFTATTKPEHEDQGLQAPAPPHAAAE SEQ ID No 639 PDLLYYPPGVVVYSGGRYDLLPSSSAY NELFIDSCCSNRYQERKEENHEKDWDQKSHDVSTDSSFEESSLFEKELE SEQ ID No 640 KFDTLRFGQLRKKIWIRMENPAYCLSAK NEFFIDSCCSYSYHGRKVEPEQEKWDEQSDQESTTSSFDEILAFYNDAS SEQ ID No 641 KFDGQPLGNFRRQLWLALDNPGYSVLSR DATDQESLELKPTSRAGIKQKGLLLSSSLMHSESELDSDDAIFTWPDREK SEQ ID No 642 GKLLHGQNGSVPNGQTPLKARSPREEIL SRGASIPGTPPTAGRVVSLSPEDAPGPSLRRSGGCSPSSDTVFGPGAP SEQ ID No 643 AAAGAEACRRENRGTLYGTRSFTVSVAQKR NKTFSPAQRHGNSGITMMRKKAKFSLRENPVEETKGEAFSDGNIEVKLC SEQ ID No 644 EQTEEKKKLKRHLALFRSELAENSPLDSGH YESHRAGCEKYEGPYPQHPFYSSASGDVIGGLSREEIRQMYESSELSRE SEQ ID No 645 EIQERMRVLELYANDPEFAAFVREQQVEEV FKNSDKEDDQEHPSEKQPSGAESGTLARASLALPTSSLSRTASQSSSH SEQ ID No 646 RGWEILRQNTLGHLNLGLNLSEGDGEEVYHF QDLKGDDTAVRDAHSKRDTKCQPQGSSGEEKGTPTTLRGGEASERKR SEQ ID No 647 PDSGCSTSKDTKYQSVYVISEEKDECVIATEV DHCVFIQRKISRPSQRPKTPLTDTSVYTELPNAEPRSKVVSCPRAPQSGL SEQ ID No 648 EGVF RDLPPLSSSEMEEFLTQESKKHENEFNEEVALTEIYKYIVKYFDEILNKLE SEQ ID No 649 RERGLEEAQKQLLHVKVLFDEKKKCKWM LGSPTSPGPGHYLRCDSTQPLLAGLTPSPKSYENLWFQASPLGTLVTPA SEQ ID No 650 PSQEDDCVFGPLLNFPLLQGIRVHGMEALGSF LSQPGPTLPKTHVKTASLGLAGKARSPLLPVSVPTAPEVSEESHKPTED SEQ ID No 651 SANVYEQDDLSEQMASLEGLMKQLNAITGSAF ATECGQGEEKSEGPLGSQESESCGLRKEEKEPHADKDFCQEKQVAYC SEQ ID No 652 PSGKPEGLNYACLTHSGYGDGSD KELILAVDGVLSVHSLHIWSLTMNQVILSAHVATAASRDSQVVRREIAKAL SEQ ID No 653 SKSFTMHSLTIQMESPVDQDPDCLFCEDPCD TSFPRLPEDEPAPAAPLRGRKDEDAFLGDPDTDPDSFLKSARLQRLPSS SEQ ID No 654 SSEMGSQDGSPLRETRKDPFSAAAAECSCRQDG LEKERELQQLGITEYLRKNIAQLQPDMEAHYPGAHEELKLMETLMYSRP SEQ ID No 655 RKVLVEQTKNEYFELKANLHAEPDYLEVLEQQT KNSLKEANHDGDFGITLAELRALMELRSTDALRKIQESYGDVYGICTKLK SEQ ID No 656 TSPNEGLSGNPADLERREAVFGKNFIPPKKPKT YNCLDFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMKKSV SEQ ID No 657 GLPVAVQCVALPWQEELCLRFMREVERLMTPEKQSS PAFDLLSRKMLGCPINDLNVILLFLRANISELISFSWLSVLCVLKDTTTQKH SEQ ID No 658 NIDTVVDFMTLLAGLEPSKPKHLTNSACDEHP SRRFQAAFQNVISSFHKQWHSQHDPQLPPAQRNIFLTECHFVELTEDIG SEQ ID No 659 PQFPCQSSMHNSHLPAALSSEQMSRTNYQSFHFNKT ELKTTRFHPNRQSSMYTVTRMESMTVVFDPNDADTTRSSRKKRATPRD SEQ ID No 660 PSFNGCSRRNSKSASATSSFISSPYTSVDEYS SRQCKQFAKDLLDQTRSSRELEIILNYRDDNSLIEEQSGNDLARLKLAIKY SEQ ID No 661 RQKEFVAQPNCQQLLASRWYDEFPGWRRRHWAVK VRKKQKAQHRCMRRVGRTGSRRSGYAFSHQEGFGELIMSGKNMRLSS SEQ ID No 662 LALSSFTTRSSSSWIESLRRKKSDSASSPSGGADKPLKG LLKLMFVNPPELPEQTTKALPVRFLFTDYNRLSSVGGETSLAEMIATLSD SEQ ID No 663 ACEREFGFLATRLFRVFKTEDTQGKKKWKKTCCLPS PPYLGKLDVSFQRACQCEGKDNRIPLLKEVFEAFPNTPINIDIKVNNNVLI SEQ ID No 664 KKVSELVKRYNREHLTVWGNANYEIVEKCYKENSD VVAAMQARHAHVPQLRWETMDVRKLDFPSASFDVVLEKGTLDALLAGE SEQ ID No 665 RDPWTVSSEGVHTVDQVLSEVGFQKGTRQLLGSRTQLE SAEVQAVLRKFDELDAVMSRLPHHSESRQEHERISRIHEEFKKKKNDPT SEQ ID No 666 FLEKKERCDYLKNKLSHIKQRIQEYDKVMNWDVQGYS AERVKELPSAGLVHYNFCTLPKRQFAPSYESRRQNQDRINKTVLYGTPR SEQ ID No 667 KCFVGQSKPNHPLLQAKPQSEPDYLEVLEKQTAISQL NLPPNPKRQQRKPKGNKNSILATEQEITYAELNLQKASQDFQGNDKTYH SEQ ID No 668 CKDLPSAPEK EKPESRTSIHNFMAHPEFRIEDSQPHIPLIDDTDLEEDAALKQNSSPPSSL SEQ ID No 669 NKNNSAIDSGINLTTDTSKSATSSSPGSPIHSLETSL EKPESRSSIHNFMTHPEFRIEDSEPHIPLIDDTDAEDDAPTKRNSSPPPSP SEQ ID No 670 NKNNNAVDSGIHLTIEMNKSATSSSPGSPLHSLETSL QGDPQRSPSSCNDLYATVKDFEKTPNSTLPPAGRPSEEPEPDYEAIQTL SEQ ID No 671 NREEEKATLGTNGHHGLVPKENDYESISDLQQGRDITRL KVAMIEPGYFKTAVTSKERFLKSFLEIWDRSSPEVKEAYGEKFVADYKKS SEQ ID No 672 AEQMEQKCTQDLSLVTNCMEHALIACHPRTRYSAGWDAK EKPESKTSIHNFMATPEFLINDYTHNIPLIDDTDVDENEERLRAPPPPSPN SEQ ID No 673 QNNNAIDSGIYLTTHVTKSATSSVFSSSPGSPLHSVETSL PAAPLAGPALPARRLSRASRPLSASQPSLPHGAPGPAASTRPASSSTPR SEQ ID No 674 LGPTPAARAAAPSPDRRDSASPGAAGGLDPQDSARSRLSSNL SKHFRKGFRTICAGLLGRAPGRASGRVCAAARGTHSGSVLERESSDLLH SEQ ID No 675 MSEAAGALRPCPGASQPCILEPCPGPSWQGPKAGDSILTVDVA SNAKIAYKQNKANTAQEQQYGSHEENLPADLEALQREIRMAQERLDLAV SEQ ID No 676 QAYSHQNNPHGPREKKAKVGSKAGSNKSTASSKSGDGKTSVWI QNEEESGEPEQAAGDAPPPYSSISAESAAYFDYKDESGFPKPPSYNVAT SEQ ID No 677 TLPSYDEAERTKAEATIPLVPGRDEDFVGRDDFDDADQLRIGNDG EGDPQTQLQDDKDPMLILRGRVPEGRALDSEVDPDPEGDLGVRGPVFG SEQ ID No 678 EPSAPPHTSGVSLGESRSSEVDVSDLGSRNYSARTDFYCLVSKDDM LLGDFLRACFVRFMNYCWCWDLEAGFPSYAEFDISGNVLGLIFNQGMIW SEQ ID No 679 MGSFYAPGLVGINVLRLLTSMYFQCWAVMSSNVPHERVFKASRSNN TIEPVQQAGCSATRLPGDGQTSAGDASLQDPPSYPPVQVIRARVSSGSS SEQ ID No 680 SEVSSINSDLEWDPEDVNLEGSKENVELLGSQVHQDSVRTAHLSDDD RRTLKQAFADCTVILCEHRIEAMLECQQFLVIEENKVRQYDSIQKLLNERS SEQ ID No 681 LFRQAISPSDRVKLFPHRNSSKCKSKPQIAALKEETEEEVQDTRL VKAFHSSLHESIQKPYNQKSIHSFMTHPEFAIEEELPRTPLLDEEEEENPD SEQ ID No 682 KASKFGTRVLLLDGEVTPYANTNNNAVDCNQVQLPQSDSSLQSLETSV NLPKGKKPAPQAAEPNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRT SEQ ID No 683 PKQPAPKPEPSFSEYASVQVPRK TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED SEQ ID No 684 QEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTV SEQ ID No 685 CVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAF GVTMWEIATRGMTPYPGVQNHEMYDYLLHGHRLKQPEDCLDELYEIMY SCWRTDPLDRPTFSVLRLQLEKLLESLPDVRNQADVIYVNTQLLESSEGL AQGSTLAPLDLNIDPDSIIASCTPRAAISVVTAEVHDSKPHEGRYILNGGS EEWEDLTSAPSAAVTAEKNSVLPGERLVRNGVSWSHSSMLPLGSSLPD ELLFADDSSEGSEVLM

TABLE 5 Examples of naturally occurring intracellular domains between ITIM and ITSM from proteins that have ITIM.*ITSM motif and vary in length from 7-1882 (Table 4 comprises SEQ ID No 686 to SEQ ID No 717) KEEEMAD SEQ ID No 686 NFHGMNPSKDTS SEQ ID No 687 HFHKVQPQEPKVTD SEQ ID No 688 ELIKPHRAAKGAPTS SEQ ID No 689 SFQMVKPWDSRGQEATD SEQ ID No 690 QVSSAESHKDLGKKDTE SEQ ID No 691 SFSEMKSREPKDQEAPST SEQ ID No 692 SFQGLRLWEPADQEAPST SEQ ID No 693 NLPKGKKPAPQAAEPNNH SEQ ID No 694 NHSVIGPNSRLARNVKEAP SEQ ID No 695 DFQWREKTPEPPVPCVPEQ SEQ ID No 696 DHLALSRPRRLSTADPADAS SEQ ID No 697 SPTNNTVYASVTHSNRETEIWTPRENDTI SEQ ID No 698 DGLRDRRSFHGPYTVQAGLPLNPMGRTGLRGRGSLSCFGPNH SEQ ID No 699 MRIKMCLIKLCKSKAKSCENDLEMGMLNSKFKKTRYQAGMRNSENLTAN SEQ ID No 700 NTLSKP QDLKGDDTAVRDAHSKRDTKCQPQGSSGEEKGTPTTLRGGEASERKR SEQ ID No 701 PDSGCSTSKD KQQMEKGPIDAITGEARYSLSEDKLIRQQIDYKTLTLHCVCPENEGSAQV SEQ ID No 702 PVKVLNCDSITQAKDKLLD TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED SEQ ID No 703 QEPTYCNMGHLSSHLPGRGPEEP EDDSDVEWKFARSKLWLSYFDDGKTLPPPFSLVPSPKSFVYFIMRIVNFP SEQ ID No 704 KCRRRRLQKDIEMGMGNSKSRLNLFTQSNSRVFESHSFNSILNQP RKVPSFTFTPTVTYQRGGEAVSSGGRPGLLNISEPAAQPWLADTWPNT SEQ ID No 705 GNNHNDCSISCCTAGNGNSDSNLTTYSRPADCIANYNNQLDNKQTNLM LPES GDQPVYLPTQMLVKFMADIASGMEYLSTKRFIHRDLAARNCMLNENMSV SEQ ID No 706 CVADFGLSKKIYNGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWSF GVTMWEIATRGQ ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTV SEQ ID No 707 CVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAF GVTMWEIATRGM FEFCDLGDLKAYLRSEQEHMRGDSQTMLLQRMACEVAAGLAAMHKLHF SEQ ID No 708 LHSDLALRNCFLTSDLNVKVGDYGIGFSRYKEDYIETDDKKVFPLRWTAP ELVTSFQDRLLTADQ LEAPVGREARKWLQLAVFCSPLVPGQSHLQLRIYFLNNTPCALQWALTN SEQ ID No 709 EQPHGGRLRGPCQLFDFNGARGDQCLKLTYISEGWENVDDSSCQLVP HLHIWHGKCPFRSFCFRRKAADENEDCSALTNEIIVTMHTFQDGLE QRSLYDRPASYKKKSMLDSEVKNLLSDDNSEGLTLLDLLSFTYQVARGM SEQ ID No 710 EFLASKNCVHRDLAARNVLLAQGKIVKICDFGLARDIMHDSNYVSKGSTF LPVKWMAPESIFDNLYTTLSDVWSYGILLWEIFSLGGTPYPGMMVDS KECAGEPLFSLFCAIKQQMEKGPIDAITGEARYSLSEDKLIRQQIDYKTLV SEQ ID No 711 LSCVSPDNANSPEVPVKILNCDTITQVKEKILDAIFKNVPCSHRPKAADMD LEWRQGSGARMILQDEDITTKIENDWKRLNTLAHYQVPDGSVVALVSKQV TVTESYTTSDTLKPSVHVHDNRPASNVVVTERVVGPISGADLHGMLEMP SEQ ID No 712 DLRDGSNVIVTERVIAPSSSLPTSLTIHHPRESSNVVVTERVIQPTSGMIG SLSMHPELANAHNVIVTERVVSGAGVTGISGTTGISGGIGSSGLVGTSMG AGSGALSGAGISGGGIGLSSLGGTASIGHMRSSSDHHFNQTIGSASPST ARSRI NPEYFSAADVYVPDEWEVAREKITMSRELGQGSFGMVYEGVAKGVVKD SEQ ID No 713 EPETRVAIKTVNEAASMRERIEFLNEASVMKEFNCHHVVRLLGVVSQGQ PTLVIMELMTRGDLKSYLRSLRPEMENNPVLAPPSLSKMIQMAGEIADG MAYLNANKFVHRDLAARNCMVAEDFTVKIGDFGMTRDIYETDYYRKGG KGLLPVRWMSPESLKDGVF GGAYVGPTQNRILRLSKELGIETYKVNVSERLVQYVKGKTYPFRGAFPP SEQ ID No 714 VWNPIAYLDYNNLWRTIDNMGKEIPTDAPWEAQHADKWDKMTMKELID KICWTKTARRFAYLFVNINVTSEPHEVSALWFLWYVKQCGGTTRIFSVTN GGQERKFVGGSGQVSERIMDLLGDQVKLNHPVTHVDQSSDNIIIETLNH EHYECKYVINAIPPTLTAKIHFRPELPAERNQLIQRLPMGAVIKCMMYYKE AFWKKKDYCGCMIIEDEDAPISITLDDTKPDGSLPAIMGFILARKADRLAK LHKEIRKKKICELYAKVLGSQEALHPVHYEEKNWCEEQYSGGCYTAYFP PGIM GGSYVGPTQNRILRLAKELGLETYKVNEVERLIHHVKGKSYPFRGPFPPV SEQ ID No 715 WNPITYLDHNNFWRTMDDMGREIPSDAPWKAPLAEEWDNMTMKELLD KLCWTESAKQLATLFVNLCVTAETHEVSALWFLWYVKQCGGTTRIISTTN GGQERKFVGGSGQVSERIMDLLGDRVKLERPVIYIDQTRENVLVETLNH EMYEAKYVISAIPPTLGMKIHFNPPLPMMRNQMITRVPLGSVIKCIVYYKE PFWRKKDYCGTMIIDGEEAPVAYTLDDTKPEGNYAAIMGFILAHKARKLA RLTKEERLKKLCELYAKVLGSLEALEPVHYEEKNWCEEQYSGGCYTTYF PPGIL KGKKFIVVCGNITVDSVTAFLRNFLRDKSGEINTEIVFLGETPPSLELETIF SEQ ID No 716 KCYLAYTTFISGSAMKWEDLRRVAVESAEACLIIANPLCSDSHAEDISNIM RVLSIKNYDSTTRIIIQILQSHNKVYLPKIPSWNWDTGDNIICFAELKLGFIA QGCLVPGLCTFLTSLFVEQNKKVMPKQTWKKHFLNSMKNKILTQRLSDD FAGMSFPEVARLCFLKMHLLLIAIEYKSLFTDGFCGLILNPPPQVRIRKNTL GFFIAETPKDVRRALFYCSVCHDDVFIPELITNCGCKSRSRQHITVPSVKR MKKCLKGISSRISGQDSPPRVSASTSSISNFTTRTLQHDVEQDSDQLDSS GMFHWCKPTSLDKVTLKRTGKSKYKFRNHIVACVFGDAHSAPMGLRNF VMPLRASNYTRKELKDIVFIGSLDYLQREWRFLWNFPQIYILPGCALYSG DLHAANIEQCSMCAVLSPPPQPSSNQTLVDTEAIMATLTIGSLQIDSSSD PSPSVSEETPGYTNGHNEKSNCRKVPILTELKNPSNIHFIEQLGGLEGSL QETNLHLSTAFSTGTVFSGSFLDSLLATAFYNYHVLELLQMLVTGGVSSQ LEQHLDKDKVYGVADSCTSLLSGRNRCKLGLLSLHETILSDVNPRNTFG QLFCGSLDLFGILCVGLYRIIDEEELNPENKRFVITRPANEFKLLPSDLVFC AIPFSTACYKRNEEFSLQKSYEIVNKASQTTETHSDTNCPPTIDSVTE ASLIRGNRSNCALFSTNLDWLVSKLDRLEASSGILEVLYCVLIESPEVLNII SEQ ID No 717 QENHIKSIISLLDKHGRNHKVLDVLCSLCVCNGVAVRSNQDLITENLLPGR ELLLQTNLINYVTSIRPNIFVGRAEGTTQYSKWYFEVMVDEVTPFLTAQA THLRVGWALTEGYTPYPGAGEGWGGNGVGDDLYSYGFDGLHLWTGH VARPVTSPGQHLLAPEDVISCCLDLSVPSISFRINGCPVQGVFESFNLDG LFFPVVSFSAGVKVRFLLGGRHGEFKFLPPPGYAPCHEAVLPRERLHLE PIKEYRREGPRGPHLVGPSRCLSHTDFVPCPVDTVQIVLPPHLERIREKL AENIHELWALTRIEQGWTYGPVRDDNKRLHPCLVDFHSLPEPERNYNLQ MSGETLKTLLALGCHVGMADEKAEDNLKKTKLPKTYMMSNGYKPAPLD LSHVRLTPAQTTLVDRLAENGHNVWARDRVGQGWSYSAVQDIPARRNP RLVPYRLLDEATKRSNRDSLCQAVRTLLGYGYNIEPPDQEPSQVENQSR CDRVRIFRAEKSYTVQSGRWYFEFEAVTTGEMRVGWARPELRPDVELG ADELAYVFNGHRGQRWHLGSEPFGRPWQPGDVVGCMIDLTENTIIFTLN GEVLMSDSGSETAFREIEIGDGFLPVCSLGPGQVGHLNLGQDVSSLRFF AICGLQEGFEPFAINMQRPVTTWFSKGLPQFEPVPLEHPHYEVSRVDGT VDTPPCLRLTHRTWGSQNSLVEMLFLRLSLPVQFHQHFRCTAGATPLAP PGLQPPAEDEARAAEPDPDYENLRRSAGGWSEAENGKEGTAKEGAPG GTPQAGGEAQPARAENEKDATTEKNKKRGFLFKAKKVAMMTQPPATPT LPRLPHDVVPADNRDDPEIILNTT

TABLE 6 Examples of naturally occurring N-terminal flanking regions of ITSM only intracellular domains that could vary in length from 0-2002 (Table 6 comprises SEQ ID No 718 to SEQ ID No 805) V AM NLMSY SEQ ID No 718 SRFKRQ SEQ ID No 719 MDDSDTP SEQ ID No 720 YGKKRNR SEQ ID No 721 KSQWIKE SEQ ID No 722 CRGLAPEE SEQ ID No 723 RLCSAMKQ SEQ ID No 724 YRKREWIKE SEQ ID No 725 RKMKRSSSEIK SEQ ID No 726 FCNMRRPAHADIK SEQ ID No 727 LRTVKRANGGELK SEQ ID No 728 MEQHVGIDVLKRDP SEQ ID No 729 LEQHVDPHVLQNKP SEQ ID No 730 RNKDVKDAIRKIIN SEQ ID No 731 VDFRPPPQGPSGPEV SEQ ID No 732 DRYFALVQPFRLTRWR SEQ ID No 733 VRMTSEIETNIVAVERI SEQ ID No 734 MERLWGLFQRAQQLSPRSSQ SEQ ID No 735 MAEPQAESEPLLGGARGGGGDWPAGL SEQ ID No 736 PETKGVALPETMKDAENLGRKAKPKEN SEQ ID No 737 MEDEAVLDRGASFLKHVCDEEEVEGHH SEQ ID No 738 YKMYGSEMLHKRDPLDEDEDTDISYKKLKEEEMAD SEQ ID No 739 RHVSDLHGLTELILLPPPCPASFNADEDDRVDILGPQPESHQQLSASSH SEQ ID No 740 CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPV SEQ ID No 741 PCVPEQ RRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKRVKVLGS SEQ ID No 742 GAFG RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA SEQ ID No 743 AEPNNH AVTISLAYSVKKMMKDNNLVRHLDACETMGNATAICSDKTGTLTTNRMT SEQ ID No 744 VVQSYLGD CCRKKRREEKYEKEVHHDIREDVPPPKSRTSTARSYIGSNHSSLGSMSP SEQ ID No 745 SNMEGYSK KRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVK SEQ ID No 746 VLGSGAFG KYLQKPMYEVQWKVVEEINGNNYVYIDPTQLPYDHKWEFPRNRLSFGK SEQ ID No 747 TLGAGAFGKVVEA YTTYPLLKESALILLQTVPKQIDIRNLIKELRNVEGVEEVHELHVWQLAGS SEQ ID No 748 RIIATAHIKCEDP AANAIAQSCQPSFYDGTIIVKKLPYLPRILGRNIGSHHVRVEHFMNHSITTL SEQ ID No 749 AKDTPLEEVVKVVTSTDV WLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPSLLYAD SEQ ID No 750 LDHLALSRPRRLSTADPADAS KKYQPYKVIKQKLEGRPETEYRKAQTFSGHEDALDDFGIYEFVAFPDVS SEQ ID No 751 GVSRIPSRSVPASDCVSGQDLHS MDEINNKIEEEKLVKANITLWEANMIKAYNASFSENSTGPPFFVHPADVP SEQ ID No 752 RGPCWETMVGQEFVRLTVSDVL KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAP SEQ ID No 753 TVEMDEELHYASLNFHGMNPSKDTS RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAG SEQ ID No 754 PISEDEQELHYAVLHFHKVQPQEPKVTD IVLRRRRKRVNTKRSSRAFRAHLRAPLKGNCTHPEDMKLCTVIMKSNGS SEQ ID No 755 FPVNRRRVEAARRAQELEMEMLSSTSPPER KARRKQAAGRPEKMDDEDPIMGTITSGSRKKPWPDSPGDQASPPGDA SEQ ID No 756 PPLEEQKELHYASLSFSEMKSREPKDQEAPST KICRKEARKRAAAEQDVPSTLGPISQGHQHECSAGSSQDHPPPGAATY SEQ ID No 757 TPGKGEEQELHYASLSFQGLRLWEPADQEAPST QRVVCQRYAGANGPFPHEYVSGTPHVPLNFIAPGGSQHGPFTGIACGK SEQ ID No 758 SMMSSVSLMGGRGGVPLYDRNHVTGASSSSSSSTKA VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQP SEQ ID No 759 PPASARSSVGEGELQYASLSFQMVKPWDSRGQEATD FVAKIARPKNRAFSIRFTDTAVVAHMDGKPNLIFQVANTRPSPLTSVRVS SEQ ID No 760 AVLYQERENGKLYQTSVDFHLDGISSDECPFFIFPL QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIY SEQ ID No 761 VAATEPVPESVQETNSI ILAKISRPKKRAKTITFSKNAVISKRGGKLCLLIRVANLRKSLLIGSHIYGKL SEQ ID No 762 LKTTVTPEGETIILDQININFVVDAGNENLFFISPL FLAKIARPKKRAETIRFSQHAVVASHNGKPCLMIRVANMRKSLLIGCQVT SEQ ID No 763 GKLLQTHQTKEGENIRLNQVNVTFQVDTASDSPFLILPL WFLKRERQEEYIEEKKRVDICRETPNICPHSGENTEYDTIPHTNRTILKED SEQ ID No 764 PAN KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHND SEQ ID No 765 DVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE LRKRRDSLSLSTQRTQGPAESARNLEYVSVSPTNNTVYASVTHSNRETE SEQ ID No 766 IWTPRENDTI RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYD SEQ ID No 767 EILQSKVLPSKEEPVN RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYD SEQ ID No 768 NDPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVK EAP KYRHKRFAVSEQGNIPHSHDWVWLGNEVELLENPVDITLPSEECTTMID SEQ ID No 769 RGLQFEERNFLLNGSSQKTFHSQLLRPSDYVYEKEIKNEPMNSSGPKRK RVKF NSSYQEIEDDSDVEWKFARSKLWLSYFDDGKTLPPPFSLVPSPKSFVYFI SEQ ID No 770 MRIVNFPKCRRRRLQKDIEMGMGNSKSRLNLFTQSNSRVFESHSFNSIL NQP WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLS SEQ ID No 771 SAQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLP GRGPEEP NNSYQEIEEDADVEWKFARAKLWLSYFDEGRTLPAPFNLVPSPKSFYYLI SEQ ID No 772 MRIKMCLIKLCKSKAKSCENDLEMGMLNSKFKKTRYQAGMRNSENLTAN NTLSKP QSVFNKRKSRVRHYLVKCPQNSSGETVTSVTSLAPLQPKKGKRQKEKP SEQ ID No 773 DIPPAVPAKAPIAPTFHKPKLLKPQRKVTLPKIAEENLTYAELELIKPHRAA KGAPTS YRHRKKRNGLTSTYAGIRKVPSFTFTPTVTYQRGGEAVSSGGRPGLLNI SEQ ID No 774 SEPAAQPWLADTWPNTGNNHNDCSISCCTAGNGNSDSNLTTYSRPAD CIANYNNQLDNKQTNLMLPES RYQRWKSKLYSIVCGKSTPEKEGELEGTTTKPLAPNPSFSPTPGFTPTL SEQ ID No 775 GFSPVPSSTFTSSSTYTPGDCPNFAAPRREVAPPYQGADPILATALASD PIPNPLQKWEDSAHKPQSLDTDDPA VRLRLQKHRPPADPCRGETETMNNLANCQREKDISVSIIGATQIKNTNKK SEQ ID No 776 ADFHGDHSADKNGFKARYPAVDYNLVQDLKGDDTAVRDAHSKRDTKC QPQGSSGEEKGTPTTLRGGEASERKRPDSGCSTSKD RAWVVFKLSSAPRLHEQRVRDIQKQVREWKEQGSKTFMCTGRPGWLT SEQ ID No 777 VSLRVGKYKKTHKNIMINLMDILEVDTKKQIVRVEPLVTMGQVTALLTSIG WTLPVLPELDDLTVGGLIMGTGIESSSHKYGLFQHIC TRDLVDDMGRHKSDRAINNRPCQILMGKSFKQKKWQDLCVGDVVCLRK SEQ ID No 778 DNIVPADMLLLASTEPSSLCYVETVDIDGETNLKFRQALMVTHKELATIKK MASFQGTVTCEAPNSRMHHFVGCLEWNDKKYSLDIGNLLLRGCRIRNTD VFDPLGGKMAPYSSAGPSHLDSHDSSQLLNGLKTAATSVWETRIKLLCC SEQ ID No 779 CIGKDDHTRVAFSSTAELFSTYFSDTDLVPSDIAAGLALLHQQQDNIRNN QEPAQVVCHAPGSSQEADLDAELENCHHYMQFAAAAYGWPLYIYRNPL TGLCRIGGDCCRSRT WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSM SEQ ID No 780 IQSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS RKRNNSRLGNGVLYASVNPEYFSAADVYVPDEWEVAREKITMSRELGQ SEQ ID No 781 GSFGMVYEGVAKGVVKDEPETRVAIKTVNEAASMRERIEFLNEASVMKE FNCHHVVRLLGVVSQGQPTLVIMELMTRGDLKSYLRSLRPEMENNPVLA PPSLSKMIQMAGEIADGMAYLNANKFVHRDLAARNCMVAEDFTVKIGDF GMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVF NKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQ SEQ ID No 782 GHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQD KMLVAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLL MVFEYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQV AAGMVYLAGLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYS KLARHSKFGMKGPASVISNDDDSASPLHHISNGSNTPSSSEGGPDAVIIG SEQ ID No 783 MTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFLA ECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFYG VCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQM LHIAQQIAAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYS NCVSCCKDPEIDFKEFEDNFDDEIDFTPPAEDTPSVQSPAEVFTLSVPNI SEQ ID No 784 SLPAPSQFQPSVEGLKSQVARHSLNYIQEIGNGWFGKVLLGEIYTGTSVA RVIVKELKASANPKEQDTFLKNGEPYYILQHPNILQCVGQCVEAIPYLLVF EFCDLGDLKAYLRSEQEHMRGDSQTMLLQRMACEVAAGLAAMHKLHFL HSDLALRNCFLTSDLNVKVGDYGIGFSRYKEDYIETDDKKVFPLRWTAPE LVTSFQDRLLTADQ YKRKTQDADRTLKRLQLQMDNLESRVALECKEAFAELQTDINELTNHMD SEQ ID No 785 EVQIPFLDYRTYAVRVLFPGIEAHPVLKELDTPPNVEKALRLFGQLLHSRA FVLTFIHTLEAQSSFSMRDRGTVASLTMVALQSRLDYATGLLKQLLADLIE KNLESKNHPKLLLRRTESVAEKMLTNWFTFLLHKFLKECAGEPLFLLYCA IKQQMEKGPIDAITGEARYSLSEDKLIRQQIDYKTLTLHCVCPENEGSAQV PVKVLNCDSITQAKDKLLD KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPA SEQ ID No 786 RQQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGH DPAPEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEES SA KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK SEQ ID No 787 LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTYLLYSRLETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAA RNCMLRDDMTVCVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADR VYTSKSDVWAFGVTMWEIATRGM SRQQRRREARGRGDASGLKRNSERKTPEGRASPAPGSGHPEGPGAHL SEQ ID No 788 DMNSLDRAQAAKNKGNKYFKAGKYEQAIQCYTEAISLCPTEKNVDLSTF YQNRAAAFEQLQKWKEVAQDCTKAVELNPKYVKALFRRAKAHEKLDNK KECLEDVTAVCILEGFQNQQSMLLADKVLKLLGKEKAKEKYKNREPLMP SPQFIKSYFSSFTDDIISQPMLKGEKSDEDKDKEGEALEVKENSGYLKAK QYMEEENYDKIISECSKEIDAEGKYMAEALLLRA LRKRRKETRFGQAFDSVMARGEPAVHFRAARSFNRERPERIEATLDSLG SEQ ID No 789 ISDELKEKLEDVLIPEQQFTLGRMLGKGEFGSVREAQLKQEDGSFVKVA VKMLKADIIASSDIEEFLREAACMKEFDHPHVAKLVGVSLRSRAKGRLPIP MVILPFMKHGDLHAFLLASRIGENPFNLPLQTLIRFMVDIACGMEYLSSRN FIHRDLAARNCMLAEDMTVCVADFGLSRKIYSGDYYRQGCASKLPVKWL ALESLADNLYTVQSDVWAFGVTMWEIMTRGQ HRRKKETRYGEVFEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEE SEQ ID No 790 LKEKLRDVMVDRHKVALGKTLGEGEFGAVMEGQLNQDDSILKVAVKTM KIAICTRSELEDFLSEAVCMKEFDHPNVMRLIGVCFQGSERESFPAPVVIL PFMKHGDLHSFLLYSRLGDQPVYLPTQMLVKFMADIASGMEYLSTKRFI HRDLAARNCMLNENMSVCVADFGLSKKIYNGDYYRQGRIAKMPVKWIAI ESLADRVYTSKSDVWSFGVTMWEIATRGQ KRIELDDSISASSSSQGLSQPSTQTTQYLRADTPNNATPITSYPTLRIEKN SEQ ID No 791 DLRSVTLLEAKGKVKDIAISRERITLKDVLQEGTFGRIFHGILIDEKDPNKE KQAFVKTVKDQASEIQVTMMLTESCKLRGLHHRNLLPITHVCIEEGEKPM VILPYMNWGNLKLFLRQCKLVEANNPQAISQQDLVHMAIQIACGMSYLA RREVIHKDLAARNCVIDDTLQVKITDNALSRDLFPMDYHCLGDNENRPVR WMALESLVNNEFSSASDVWAFGVTLWELMTLGQ NCRTWWQVLDSLLNSQRKRLHNAASKLHKLKSEGFMKVLKCEVELMAR SEQ ID No 792 MAKTIDSFTQNQTRLVVIIDGLDACEQDKVLQMLDTVRVLFSKGPFIAIFA SDPHIIIKAINQNLNSVLRDSNINGHDYMRNIVHLPVFLNSRGLSNARKFL VTSATNGDVPCSDTTGIQEDADRRVSQNSLGEMTKLGSKTALNRRDTY RRRQMQRTITRQMSFDLTKLLVTEDWFSDISPQTMRRLLNIVSVTGRLLR ANQISFNWDRLASWINLTEQWPYRTSWLILYLEETEGIPDQMTLK MFNYTFQQVQEHTDQIWKFQRHDLIEEYHGRPAAPPPFILLSHLQLFIKR SEQ ID No 793 VVLKTPAKRHKQLKNKLEKNEEAALLSWEIYLKENYLQNRQFQQKQRPE QKIEDISNKVDAMVDLLDLDPLKRSGSMEQRLASLEEQVAQTAQALHWI VRTLRASGFSSEADVPTLASQKAAEEPDAEPGGRKKTEEPGDSYHVNA RHLLYPNCPVTRFPVPNEKVPWETEFLIYDPPFYTAERKDAAAMDPMGD TLEPLSTIQYNVVDGLRDRRSFHGPYTVQAGLPLNPMGRTGLRGRGSLS CFGPNH AYKRKSRESDLTLKRLQMQMDNLESRVALECKEAFAELQTDIHELTSDL SEQ ID No 794 DGAGIPFLDYRTYTMRVLFPGIEDHPVLRDLEVPGYRQERVEKGLKLFA QLINNKVFLLSFIRTLESQRSFSMRDRGNVASLIMTVLQSKLEYATDVLKQ LLADLIDKNLESKNHPKLLLRRTESVAEKMLTNWFTFLLYKFLKECAGEPL FSLFCAIKQQMEKGPIDAITGEARYSLSEDKLIRQQIDYKTLVLSCVSPDN ANSPEVPVKILNCDTITQVKEKILDAIFKNVPCSHRPKAADMDLEWRQGS GARMILQDEDITTKIENDWKRLNTLAHYQVPDGSVVALVSKQV RWHCPRRLLGACWTLNGQEEPVSQPTPQLENEVSRQHLPATLPEMVA SEQ ID No 795 FYQELHTPTQGQTMVRQLMHKLLVFSAREVDHRGGCLMLQDTGISLLIP PGAVAVGRQERVSLILVWDLSDAPSLSQAQGLVSPVVACGPHGASFLK PCTLTFKHCAEQPSHARTYSSNTTLLDAKVWRPLGRPGAHASRDECRIH LSHFSLYTCVLEAPVGREARKWLQLAVFCSPLVPGQSHLQLRIYFLNNTP CALQWALTNEQPHGGRLRGPCQLFDFNGARGDQCLKLTYISEGWENV DDSSCQLVPHLHIWHGKCPFRSFCFRRKAADENEDCSALTNEIIVTMHT FQDGLE KQKPRYEIRWRVIESISPDGHEYIYVDPMQLPYDSRWEFPRDGLVLGRV SEQ ID No 796 LGSGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQALMSELKI MTHLGPHLNIVNLLGACTKSGPIYIITEYCFYGDLVNYLHKNRDSFLSHHP EKPKKELDIFGLNPADESTRSYVILSFENNGDYMDMKQADTTQYVPMLE RKEVSKYSDIQRSLYDRPASYKKKSMLDSEVKNLLSDDNSEGLTLLDLLS FTYQVARGMEFLASKNCVHRDLAARNVLLAQGKIVKICDFGLARDIMHD SNYVSKGSTFLPVKWMAPESIFDNLYTTLSDVWSYGILLWEIFSLGGTPY PGMMVDS CCCKQRQPEGLGTRFAPVPEGGEGVMQSWRIEGAHPEDRDVSNICAP SEQ ID No 797 MTASNTQDRMDSSEIYTNTYAAGGTVEGGVSGVELNTGMGTAVGLMAA GAAGASGAARKRSSTMGTLRDYADADINMAFLDSYFSEKAYAYADEDE GRPANDCLLIYDHEGVGSPVGSIGCCSWIVDDLDESCMETLDPKFRTLA EICLNTEIEPFPSHQACIPISTDLPLLGPNYFVNESSGLTPSEVEFQEEMA ASEPVVHGDIIVTETYGNADPCVQPTTIIFDPQLAPNVVVTEAVMAPVYDI QGNICVPAELADYNNVIYAERVLASPGVPDMSNSSTTEGCMGPVMSGNI LVGPEIQVMQMMSPDLPIGQTVGSTSPMTSRHRV SNKCDVVVVGGGISGMAAAKLLHDSGLNVVVLEARDRVGGRTYTLRNQ SEQ ID No 798 KVKYVDLGGSYVGPTQNRILRLAKELGLETYKVNEVERLIHHVKGKSYPF RGPFPPVWNPITYLDHNNFWRTMDDMGREIPSDAPWKAPLAEEWDNM TMKELLDKLCWTESAKQLATLFVNLCVTAETHEVSALWFLWYVKQCGG TTRIISTTNGGQERKFVGGSGQVSERIMDLLGDRVKLERPVIYIDQTREN VLVETLNHEMYEAKYVISAIPPTLGMKIHFNPPLPMMRNQMITRVPLGSVI KCIVYYKEPFWRKKDYCGTMIIDGEEAPVAYTLDDTKPEGNYAAIMGFIL AHKARKLARLTKEERLKKLCELYAKVLGSLEALEPVHYEEKNWCEEQYS GGCYTTYFPPGIL MENQEKASIAGHMFDVVVIGGGISGLSAAKLLTEYGVSVLVLEARDRVG SEQ ID No 799 GRTYTIRNEHVDYVDVGGAYVGPTQNRILRLSKELGIETYKVNVSERLVQ YVKGKTYPFRGAFPPVWNPIAYLDYNNLWRTIDNMGKEIPTDAPWEAQH ADKWDKMTMKELIDKICWTKTARRFAYLFVNINVTSEPHEVSALWFLWY VKQCGGTTRIFSVTNGGQERKFVGGSGQVSERIMDLLGDQVKLNHPVT HVDQSSDNIIIETLNHEHYECKYVINAIPPTLTAKIHFRPELPAERNQLIQRL PMGAVIKCMMYYKEAFWKKKDYCGCMIIEDEDAPISITLDDTKPDGSLPA IMGFILARKADRLAKLHKEIRKKKICELYAKVLGSQEALHPVHYEEKNWC EEQYSGGCYTAYFPPGIM CCDCGGAPRSAAGFEPVPECSDGAIHSWAVEGPQPEPRDITTVIPQIPP SEQ ID No 800 DNANIIECIDNSGVYTNEYGGREMQDLGGGERMTGFELTEGVKTSGMP EICQEYSGTLRRNSMRECREGGLNMNFMESYFCQKAYAYADEDEGRP SNDCLLIYDIEGVGSPAGSVGCCSFIGEDLDDSFLDTLGPKFKKLADISLG KESYPDLDPSWPPQSTEPVCLPQETEPVVSGHPPISPHFGTTTVISESTY PSGPGVLHPKPILDPLGYGNVTVTESYTTSDTLKPSVHVHDNRPASNVV VTERVVGPISGADLHGMLEMPDLRDGSNVIVTERVIAPSSSLPTSLTIHHP RESSNVVVTERVIQPTSGMIGSLSMHPELANAHNVIVTERVVSGAGVTGI SGTTGISGGIGSSGLVGTSMGAGSGALSGAGISGGGIGLSSLGGTASIG HMRSSSDHHFNQTIGSASPSTARSRI NLEGVMNQADAPRPLNWTIRKLCHAAFLPSVRLLKAQKSWIERAFYKRE SEQ ID No 801 CVHIIPSTKDPHRCCCGRLIGQHVGLTPSISVLQNEKNESRLSRNDIQSE KWSISKHTQLSPTDAFGTIEFQGGGHSNKAMYVRVSFDTKPDLLLHLMT KEWQLELPKLLISVHGGLQNFELQPKLKQVFGKGLIKAAMTTGAWIFTGG VNTGVIRHVGDALKDHASKSRGKICTIGIAPWGIVENQEDLIGRDVVRPY QTMSNPMSKLTVLNSMHSHFILADNGTTGKYGAEVKLRRQLEKHISLQKI NTRCLPFFSLDSRLFYSFWGSCQLDSVGIGQGVPVVALIVEGGPNVISIV LEYLRDTPPVPVVVCDGSGRASDILAFGHKYSEEGGLINESLRDQLLVTI QKTFTYTRTQAQHLFIILMECMKKKELITVFRMGSEGHQDIDLAILTALLK GANASAPDQLSLALAWNRVDIARSQIFIYGQQWPVGSLEQAMLDALVLD RVDFVKLLIENGVSMHRFLTISRLEELYNTRHGPSN ELFANKRKYTSSYEALKGKKFIVVCGNITVDSVTAFLRNFLRDKSGEINTE SEQ ID No 802 IVFLGETPPSLELETIFKCYLAYTTFISGSAMKWEDLRRVAVESAEACLIIA NPLCSDSHAEDISNIMRVLSIKNYDSTTRIIIQILQSHNKVYLPKIPSWNWD TGDNIICFAELKLGFIAQGCLVPGLCTFLTSLFVEQNKKVMPKQTWKKHF LNSMKNKILTQRLSDDFAGMSFPEVARLCFLKMHLLLIAIEYKSLFTDGFC GLILNPPPQVRIRKNTLGFFIAETPKDVRRALFYCSVCHDDVFIPELITNCG CKSRSRQHITVPSVKRMKKCLKGISSRISGQDSPPRVSASTSSISNFTTR TLQHDVEQDSDQLDSSGMFHWCKPTSLDKVTLKRTGKSKYKFRNHIVA CVFGDAHSAPMGLRNFVMPLRASNYTRKELKDIVFIGSLDYLQREWRFL WNFPQIYILPGCALYSGDLHAANIEQCSMCAVLSPPPQPSSNQTLVDTE AIMATLTIGSLQIDSSSDPSPSVSEETPGYTNGHNEKSNCRKVPILTELKN PSNIHFIEQLGGLEGSLQETNLHLSTAFSTGTVFSGSFLDSLLATAFYNYH VLELLQMLVTGGVSSQLEQHLDKDKVYGVADSCTSLLSGRNRCKLGLLS LHETILSDVNPRNTFGQLFCGSLDLFGILCVGLYRIIDEEELNPENKRFVIT RPANEFKLLPSDLVFCAIPFSTACYKRNEEFSLQKSYEIVNKASQTTETH SDTNCPPTIDSVTE QFEELVYLWMERQKSGGNYSRHRAQTEKHVVLCVSSLKIDLLMDFLNEF SEQ ID No 803 YAHPRLQDYYVVILCPTEMDVQVRRVLQIPLWSQRVIYLQGSALKDQDL MRAKMDNGEACFILSSRNEVDRTAADHQTILRAWAVKDFAPNCPLYVQI LKPENKFHVKFADHVVCEEECKYAMLALNCICPATSTLITLLVHTSRGQE GQESPEQWQRMYGRCSGNEVYHIRMGDSKFFREYEGKSFTYAAFHAH KKYGVCLIGLKREDNKSILLNPGPRHILAASDTCFYINITKEENSAFIFKQE EKRKKRAFSGQGLHEGPARLPVHSIIASMGTVAMDLQGTEHRPTQSGG GGGGSKLALPTENGSGSRRPSIAPVLELADSSALLPCDLLSDQSEDEVT PSDDEGLSVVEYVKGYPPNSPYIGSSPTLCHLLPVKAPFCCLRLDKGCK HNSYEDAKAYGFKNKLIIVSAETAGNGLYNFIVPLRAYYRSRKELNPIVLL LDNKPDHHFLEAICCFPMVYYMEGSVDNLDSLLQCGIIYADNLVVVDKES TMSAEEDYMADAKTIVNVQTMFRLFPSLSITTELTHPSNMRFMQFRAKD SYSLALSKLEKRERENGSNLAFMFRLPFAAGRVFSISMLDTLLYQSFVKD YMITITRLLLGLDTTPGSGYLCAMKITEGDLWIRTYGRLFQKLCSSSAEIPI GIYRTESHVFSTSESQISVNVEDCEDTREVKGPWGSRAGTGGSSQGRH TGGGDPAEHPLLRRKSLQWARRLSRKAPKQAGRAAAAEWISQQRLSLY RRSERQELSELVKNRMKHLGLPT MSGGASATGPRRGPPGLEDTTSKKKQKDRANQESKDGDPRKETGSRY SEQ ID No 804 VAQAGLEPLASGDPSASASHAAGITGSRHRTRLFFPSSSGSASTPQEEQ TKEGACEDPHDLLATPTPELLLDWRQSAEEVIVKLRVGVGPLQLEDVDA AFTDTDCVVRFAGGQQWGGVFYAEIKSSCAKVQTRKGSLLHLTLPKKVP MLTWPSLLVEADEQLCIPPLNSQTCLLGSEENLAPLAGEKAVPPGNDPV SPAMVRSRNPGKDDCAKEEMAVAADAATLVDEPESMVNLAFVKNDSYE KGPDSVVVHVYVKEICRDTSRVLFREQDFTLIFQTRDGNFLRLHPGCGP HTTFRWQVKLRNLIEPEQCTFCFTASRIDICLRKRQSQRWGGLEAPAAR VGGAKVAVPTGPTPLDSTPPGGAPHPLTGQEEARAVEKDKSKARSEDT GLDSVATRTPMEHVTPKPETHLASPKPTCMVPPMPHSPVSGDSVEEEE EEEKKVCLPGFTGLVNLGNTCFMNSVIQSLSNTRELRDFFHDRSFEAEIN YNNPLGTGGRLAIGFAVLLRALWKGTHHAFQPSKLKAIVASKASQFTGY AQHDAQEFMAFLLDGLHEDLNRIQNKPYTETVDSDGRPDEVVAEEAWQ RHKMRNDSFIVDLFQGQYKSKLVCPVCAKVSITFDPFLYLPVPLPQKQKV LPVFYFAREPHSKPIKFLVSVSKENSTASEVLDSLSQSVHVKPENLRLAE VIKNRFHRVFLPSHSLDTVSPSDTLLCFELLSSELAKERVVVLEVQQRPQ VPSVPISKCAACQRKQQSEDEKLKRCTRCYRVGYCNQLCQKTHWPDH KGLCRPENIGYPFLVSVPASRLTYARLAQLLEGYARYSVSVFQPPFQPG RMALESQSPGCTTLLSTGSLEAGDSERDPIQPPELQLVTPMAEGDTGLP RVWAAPDRGPVPSTSGISSEMLASGPIEVGSLPAGERVSRPEAAVPGY QHPSEAMNAHTPQFFIYKIDSSNREQRLEDKGDTPLELGDDCSLALVWR NNERLQEFVLVASKELECAEDPGSAGEAARAGHFTLDQCLNLFTRPEVL APEEAWYCPQCKQHREASKQLLLWRLPNVLIVQLKRFSFRSFIWRDKIN DLVEFPVRNLDLSKFCIGQKEEQLPSYDLYAVINHYGGMIGGHYTACARL PNDRSSQRSDVGWRLFDDSTVTTVDESQVV MADGGEGEDEIQFLRTDDEVVLQCTATIHKEQQKLCLAAEGFGNRLCFL SEQ ID No 805 ESTSNSKNVPPDLSICTFVLEQSLSVRALQEMLANTVEKSEGQVDVEKW KFMMKTAQGGGHRTLLYGHAILLRHSYSGMYLCCLSTSRSSTDKLAFDV GLQEDTTGEACWWTIHPASKQRSEGEKVRVGDDLILVSVSSERYLHLSY GNGSLHVDAAFQQTLWSVAPISSGSEAAQGYLIGGDVLRLLHGHMDEC LTVPSGEHGEEQRRTVHYEGGAVSVHARSLWRLETLRVAWSGSHIRW GQPFRLRHVTTGKYLSLMEDKNLLLMDKEKADVKSTAFTFRSSKEKLDV GVRKEVDGMGTSEIKYGDSVCYIQHVDTGLWLTYQSVDVKSVRMGSIQ RKAIMHHEGHMDDGISLSRSQHEESRTARVIRSTVFLFNRFIRGLDALSK KAKASTVDLPIESVSLSLQDLIGYFHPPDEHLEHEDKQNRLRALKNRQNL FQEEGMINLVLECIDRLHVYSSAAHFADVAGREAGESWKSILNSLYELLA ALIRGNRKNCAQFSGSLDWLISRLERLEASSGILEVLHCVLVESPEALNIIK EGHIKSIISLLDKHGRNHKVLDVLCSLCVCHGVAVRSNQHLICDNLLPGR DLLLQTRLVNHVSSMRPNIFLGVSEGSAQYKKWYYELMVDHTEPFVTAE ATHLRVGWASTEGYSPYPGGGEEWGGNGVGDDLFSYGFDGLHLWSG CIARTVSSPNQHLLRTDDVISCCLDLSAPSISFRINGQPVQGMFENFNIDG LFFPVVSFSAGIKVRFLLGGRHGEFKFLPPPGYAPCYEAVLPKEKLKVEH SREYKQERTYTRDLLGPTVSLTQAAFTPIPVDTSQIVLPPHLERIREKLAE NIHELWVMNKIELGWQYGPVRDDNKRQHPCLVEFSKLPEQERNYNLQM SLETLKTLLALGCHVGISDEHAEDKVKKMKLPKNYQLTSGYKPAPMDLSF IKLTPSQEAMVDKLAENAHNVWARDRIRQGWTYGIQQDVKNRRNPRLV PYTLLDDRTKKSNKDSLREAVRTLLGYGYNLEAPDQDHAARAEVCSGT GERFRIFRAEKTYAVKAGRWYFEFETVTAGDMRVGWSRPGCQPDQEL GSDERAFAFDGFKAQRWHQGNEHYGRSWQAGDVVGCMVDMNEHTM MFTLNGEILLDDSGSELAFKDFDVGDGFIPVCSLGVAQVGRMNFGKDVS TLKYFTICGLQEGYEPFAVNTNRDITMWLSKRLPQFLQVPSNHEHIEVTRI DGTIDSSPCLKVTQKSFGSQNSNTDIMFYRLSMPIECAEVFSKTVAGGLP GAGLFGPKNDLEDYDADSDFEVLMKTAHGHLVPDRVDKDKEATKPEFN NHKDYAQEKPSRLKQRFLLRRTKPDYSTSHSARLTEDVLADDRDDYDFL MQTS

TABLE 7 Naturally occurring C-terminal flanking regions of ITIM.*ITSM intracellular domains varying in length from 1-2890 (Table 7 comprises SEQ ID No 806 to SEQ ID No 836) V SRP RTQ KIHK SEQ ID No 806 KTSK SEQ ID No 807 KIHR SEQ ID No 808 CVRS SEQ ID No 809 QYSK SEQ ID No 810 LFEENKL SEQ ID No 811 KAENIIMMETAQTSL SEQ ID No 812 YVISEEKDECVIATEV SEQ ID No 813 NHSKESKPTFSRATALDNV SEQ ID No 814 RKAVPDAVESRYSRTEGSLDGT SEQ ID No 815 KIHTGQPLRGPGFGLQLEREMSGMVPK SEQ ID No 816 VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL SEQ ID No 817 QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK SEQ ID No 818 YSYQPRTNSLSFPKQIAWNQSRTNSIISSQIPLGDNAKENERKTSDEVYD SEQ ID No 819 EDPFAYSEPL MKRLIKRYVLKAQVDKENDEVNEGELKEIKQDISSLRYELLEDKSQATEE SEQ ID No 820 LAILIHKLSEKLNPSMLRCE IRQPVGRIFFAGTETATKWSGYMEGAVEAGERAAREVLNGLGKVTEKDI SEQ ID No 821 WVQEPESKDVPAVEITHTFWERNLPS LRQPVDRIYFAGTETATHWSGYMEGAVEAGERAAREILHAMGKIPEDEI SEQ ID No 822 WQSEPESVDVPAQPITTTFLERHLPSV MKRLIKRYVLKAQVDRENDEVNEGELKEIKQDISSLRYELLEEKSQATGE SEQ ID No 823 LADLIQQLSEKFGKNLNKDHLRVNKGKDI LFYRRRNSPVERPPRAGHSEHHPDLGPAAEAAASQASRIWQELEAEEE SEQ ID No 824 PVPEGSGPLGPWGPQDWVGPLPRGPTTPDEGCLRY LRFQASEEESWAAPPPVSQPPPCNRLPPELFEQLRMLLEPNSITGNDW SEQ ID No 825 RRLASHLGLCGMKIRFLSCQRSPAAAILELFEEQNGSLQELHYLMTVME RLDCASAIQNYLSGTHGGSPGPERGGARDNQGLELDEKL ENSEIYDYLRQGNRLKQPADCLDGLYALMSRCWELNPQDRPSFTELRE SEQ ID No 826 DLENTLKALPPAQEPDEILYVNMDEGGGYPEPPGAAGGADPPTQPDPK DSCSCLTAAEVHPAGRYVLCPSTTPSPAQPADRGSPAAPGQEDGA TRWRRNEDGAICRKSIKKMLEVLVVKLPLSEHWALPGGSREPGEMLPR SEQ ID No 827 KLKRILRQEHWPSFENLLKCGMEVYKGYMDDPRNTDNAWIETVAVSVH FQDQNDVELNRLNSNLHACDSGASIRWQVVDRRIPLYANHKTLLQKAAA EFGAHY WSFGVVLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFE SEQ ID No 828 LMRMCWQYNPKMRPSFLEIISSIKEEMEPGFREVSFYYSEENKLPEPEE LDLEPENMESVPLDPSASSSSLPLPDRHSGHKAENGPGPGVLVLRASFD ERQPYAHMNGGRKNERALPLPQSSTC KSGYRMAKPDHATSEVYEIMVKCWNSEPEKRPSFYHLSEIVENLLPGQY SEQ ID No 829 KKSYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEEDKLKDWEGGL DEQRLSADSGYIIPLPDIDPVPEEEDLGKRNRHSSQTSEESAIETGSSSS TFIKREDETIEDIDMMDDIGIDSSDLVEDSFL QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRL SEQ ID No 830 QLEKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSII ASCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAE KNSVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM CETLQFLDCICGSTTGGLGLLGLYINEKNVALINQTLESLTEYCQGPCHE SEQ ID No 831 NQNCIATHESNGIDIITALILNDINPLGKKRMDLVLELKNNASKLLLAIMESR HDSENAERILYNMRPKELVEVIKKAYMQGEVEFEDGENGEDGAASPRN VGHNIYILAHQLARHNKELQSMLKPGGQVDGDEALEFYAKHTAQIEIVRL DRTMEQIVFPVPSICEFLTKESKLRIYYTTERDEQGSKINDFFLRSEDLFN EMNWQKKLRAQPVLYWCARNMS CETLQFLDCICGSTTGGLGLLGLYINEKNVALVNQNLESLTEYCQGPCHE SEQ ID No 832 NQTCIATHESNGIDIIIALILNDINPLGKYRMDLVLQLKNNASKLLLAIMESR HDSENAERILFNMRPRELVDVMKNAYNQGLECDHGDDEGGDDGVSPK DVGHNIYILAHQLARHNKLLQQMLKPGSDPDEGDEALKYYANHTAQIEIV RHDRTMEQIVFPVPNICEYLTRESKCRVFNTTERDEQGSKVNDFFQQTE DLYNEMKWQKKIRNNPALFWFSRHIS NNSTVSRTSASKYENMIRYTGSPDSLRSRTPMITPDLESGVKMWHLVKN SEQ ID No 833 HEHGDQKEGDRGSKMVSEIYLTRLLATKGTLQKFVDDLFETIFSTAHRG SALPLAIKYMFDFLDEQADKHGIHDPHVRHTWKSNCLPLRFWVNMIKNP QFVFDIHKNSITDACLSVVAQTFMDSCSTSEHRLGKDSPSNKLLYAKDIP SYKNWVERYYSDIGKMPAISDQDMNAYLAEQSRMHMNEFNTMSALSEI FSYVGKYSEEILGPLDHDDQCGKQKLAYKLEQVITLMSLDS CETLQFLDIMCGSTTGGLGLLGLYINEDNVGLVIQTLETLTEYCQGPCHE SEQ ID No 834 NQTCIVTHESNGIDIITALILNDISPLCKYRMDLVLQLKDNASKLLLALMES RHDSENAERILISLRPQELVDVIKKAYLQEEERENSEVSPREVGHNIYILA LQLSRHNKQLQHLLKPVKRIQEEEAEGISSMLSLNNKQLSQMLKSSAPA QEEEEDPLAYYENHTSQIEIVRQDRSMEQIVFPVPGICQFLTEETKHRLF TTTEQDEQGSKVSDFFDQSSFLHNEMEWQRKLRSMPLIYWFSRRMT PYSQRPKAEDMDLEWRQGRMTRIILQDEDVTTKIECDWKRLNSLAHYQ SEQ ID No 835 VTDGSLVALVPKQVSAYNMANSFTFTRSLSRYESLLRTASSPDSLRSRA PMITPDQETGTKLWHLVKNHDHADHREGDRGSKMVSEIYLTRLLATKGT LQKFVDDLFETVFSTAHRGSALPLAIKYMFDFLDEQADQRQISDPDVRHT WKSNCLPLRFWVNVIKNPQFVFDIHKNSITDACLSVVAQTFMDSCSTSE HRLGKDSPSNKLLYAKDIPNYKSWVERYYRDIAKMASISDQDMDAYLVE QSRLHASDFSVLSALNELYFYVTKYRQEILTALDRDASCRKHKLRQKLEQ IISLVSSDS DLSNKINEMKTFNSPNLKDGRFVNPSGQPTPYATTQLIQSNLSNNMNNG SEQ ID No 836 SGDSGEKHWKPLGQQKQEVAPVQYNIVEQNKLNKDYRANDTVPPTIPY NQSYDQNTGGSYNSSDRGSSTSGSQGHKKGARTPKVPKQGGMNWAD LLPPPPAHPPPHSNSEEYNISVDESYDQEMPCPVPPARMYLQQDELEEE EDERGPTPPVRGAASSPAAVSYSHQSTATLTPSPQEELQPMLQDCPEE TGHMQHQPDRRRQPVSPPPPPRPISPPHTYGYISGPLVSDMDTDAPEE EEDEADMEVAKMQTRRLLLRGLEQTPASSVGDLESSVTGSMINGWGSA SEEDNISSGRSSVSSSDGSFFTDADFAQAVAAAAEYAGLKVARRQMQD AAGRRHFHASQCPRPTSPVSTDSNMSAAVMQKTRPAKKLKHQPGHLR RETYTDDLPPPPVPPPAIKSPTAQSKTQLEVRPVVVPKLPSMDARTDRS SDRKGSSYKGREVLDGRQVVDMRTNPGDPREAQEQQNDGKGRGNKA AKRDLPPAKTHLIQEDILPYCRPTFPTSNNPRDPSSSSSMSSRGSGSRQ REQANVGRRNIAEMQVLGGYERGEDNNEELEETES

TABLE 8 Examples of naturally occurring C-terminal flanking regions of ITSM only intracellular domains that could vary in length from 1-2890 (Table 8 comprises SEQ ID No 837 to SEQ ID No 925) L V PR RIN RTQ SRP KIHK SEQ ID No 837 KTSK SEQ ID No 838 KIHR SEQ ID No 839 CVRS SEQ ID No 840 QYSK SEQ ID No 841 HYTQQ SEQ ID No 842 LGPKPQG SEQ ID No 843 LFEENKL SEQ ID No 844 VKADTYCA SEQ ID No 845 QTSEPSGT SEQ ID No 846 QSCALPTDAL SEQ ID No 847 AKNALLRWRV SEQ ID No 848 SKNRLLSIKT SEQ ID No 849 QHIPAQQQDHPE SEQ ID No 850 AHHRFYTKRLTFWT SEQ ID No 851 AHHRFYAKRMTLWT SEQ ID No 852 KHRHWYPFNFVIEQ SEQ ID No 853 AHHRFYAERLAGWPC SEQ ID No 854 KAENIIMMETAQTSL SEQ ID No 855 YVISEEKDECVIATEV SEQ ID No 856 RKAVPDAVESRYSRTEGSLDGT SEQ ID No 857 RKPQVVPPPQQNDLEIPESPTYENFT SEQ ID No 2028 GKSQPKAQNPARLSRKELENFDVYS SEQ ID No 2029 KIHTGQPLRGPGFGLQLEREMSGMVPK SEQ ID No 858 IYAGFDTKIMKNCGKIHLKRTKLDLLMNKL SEQ ID No 859 ASALKSHRTRGHGRGDCCGRSLGDSCCFSAK SEQ ID No 860 FTLVLEEIRQGFFTDEDTHLVKKFTLYVGDNWNKCD SEQ ID No 861 VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL SEQ ID No 862 PSEDFERTPQSPTLPPAKVAAPNLSRMGAIPVMIPAQSKDGSIV SEQ ID No 863 LPEDGGPYTNSILFDSDDNIKWVCQDMGLGDSQDFRDYMESLQDQM SEQ ID No 864 QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK SEQ ID No 865 SYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSK SEQ ID No 866 HDYV QVGPGAAARWDLCIDQAVVFIEDAIQYRSINHRVDASSMWLYRRYYSNV SEQ ID No 867 CQR EGPRKGHLEEEEEDGEEGAETLAHFCPMELRGPEPLGSRPRQPNLIPW SEQ ID No 868 AAAGRRAAP QKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES SEQ ID No 869 YSYQPRTNSLSFPKQIAWNQSRTNSIISSQIPLGDNAKENERKTSDEVYD SEQ ID No 870 EDPFAYSEPL DPFEMAAYLKDGYRIAQPINCPDELFAVMACCWALDPEERPKFQQLVQ SEQ ID No 871 CLTEFHAALGAYV THSNRETEIWTPRENDTITIYSTINHSKESKPTFSRATALDNV SEQ ID No 872 MKRLIKRYVLKAQVDKENDEVNEGELKEIKQDISSLRYELLEDKSQATEE SEQ ID No 873 LAILIHKLSEKLNPSMLRCE PPSHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPN SEQ ID No 874 GKTRTSLKTMSRRKLSQQKEKKATQ IRQPVGRIFFAGTETATKWSGYMEGAVEAGERAAREVLNGLGKVTEKDI SEQ ID No 875 WVQEPESKDVPAVEITHTFWERNLPS FNLQGKTPVSQKEESSATIYCSIRKPQVVPPPQQNDLEIPESPTYENFT SEQ ID No 876 LRQPVDRIYFAGTETATHWSGYMEGAVEAGERAAREILHAMGKIPEDEI SEQ ID No 877 WQSEPESVDVPAQPITTTFLERHLPSV PHTNRTILKEDPANTVYSTVEIPKKMENPHSLLTMPDTPRLFAYENVI SEQ ID No 878 MKRLIKRYVLKAQVDRENDEVNEGELKEIKQDISSLRYELLEEKSQATGE SEQ ID No 879 LADLIQQLSEKFGKNLNKDHLRVNKGKDI LFYRRRNSPVERPPRAGHSEHHPDLGPAAEAAASQASRIWQELEAEEE SEQ ID No 880 PVPEGSGPLGPWGPQDWVGPLPRGPTTPDEGCLRY ANLTASDVMNRVNLGYLQDEMNDHQNTLSYVLINPPPDTRLEPSDIVYLI SEQ ID No 881 RSDPLAHVASSSQSRKSSCSHKLSSCNPETRDETQL MASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQ SEQ ID No 882 DSKPPGTSSYEIVI ENVPPLRWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRT SEQ ID No 883 PRREATLELLGRVLRDMDLLGCLEDIEEALCGPAALPPAPSLLR LIGDFLRACFVRFCNYCWCWDLEYGYPSYTEFDISGNVLALIFNQGMIW SEQ ID No 884 MGSFFAPSLPGINILRLHTSMYFQCWAVMCCNVPEARVFKASRSNN ESTESQILVGIVQRAQLVQALQAEPPSRAPGHQQCLQDILARGCPTEPV SEQ ID No 885 TLTLFSETTLHQAQNLFKLLNLQSLFVTSRGRAVGCVSWVEMKKAISNLT NPPAPK AKTIKDVFHNHGIHATTIQPEFASVGSKSSVVPCELACRTQCALKQCCGT SEQ ID No 886 LPQAPSGKDAEKTPAVSISCLELSNNLEKKPRRTKAENIPAVVIEIKNMPN KQPESSL TPSSPLATLLQHENPSHFELVVFLSAMQEGTGEICQRRTSYLPSEIMLHH SEQ ID No 887 CFASLLTRGSKGEYQIKMENFDKTVPEFPTPLVSKSPNRTDLDIHINGQSI DNFQISETGLTE GGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLS SEQ ID No 888 NTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARL QALAQAPPVYLDVLG GGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQL SEQ ID No 889 SNNEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTL LQNLAKASPVYLDILG LNPPPSPATDPSLYNMDMFYSSNIPATARPYRPYIIRGMAPPTTPCSTDV SEQ ID No 890 CDSDYSASRWKASKYYLDLNSDSDPYPPPPTPHSQYLSAEDSCPPSPA TERSYFHLFPPPPSPCTDSS DHNSPFFHMAAETLLQQDFELVVFLDGTVESTSATCQVRTSYVPEEVLW SEQ ID No 891 GYRFAPIVSKTKEGKYRVDFHNFSKTVEVETPHCAMCLYNEKDVRARM KRGYDNPNFILSEVNETDDTKM DETSPLKDLPLRSGEGDFELVLILSGTVESTSATCQVRTSYLPEEILWGY SEQ ID No 892 EFTPAISLSASGKYIADFSLFDQVVKVASPSGLRDSTVRYGDPEKLKLEE SLREQAEKEGSALSVRISNV LRFQASEEESWAAPPPVSQPPPCNRLPPELFEQLRMLLEPNSITGNDW SEQ ID No 893 RRLASHLGLCGMKIRFLSCQRSPAAAILELFEEQNGSLQELHYLMTVME RLDCASAIQNYLSGTHGGSPGPERGGARDNQGLELDEKL TRWRRNEDGAICRKSIKKMLEVLVVKLPLSEHWALPGGSREPGEMLPR SEQ ID No 894 KLKRILRQEHWPSFENLLKCGMEVYKGYMDDPRNTDNAWIETVAVSVH FQDQNDVELNRLNSNLHACDSGASIRWQVVDRRIPLYANHKTLLQKAAA EFGAHY ENAEIYNYLIGGNRLKQPPECMEDVYDLMYQCWSADPKQRPSFTCLRM SEQ ID No 895 ELENILGQLSVLSASQDPLYINIERAEEPTAGGSLELPGRDQPYSGAGDG SGMGAVGGTPSDCRYILTPGGLAEQPGQAEHQPESPLNETQRLLLLQQ GLLPHSSC WSFGVVLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFE SEQ ID No 896 LMRMCWQYNPKMRPSFLEIISSIKEEMEPGFREVSFYYSEENKLPEPEE LDLEPENMESVPLDPSASSSSLPLPDRHSGHKAENGPGPGVLVLRASFD ERQPYAHMNGGRKNERALPLPQSSTC KSGYRMAKPDHATSEVYEIMVKCWNSEPEKRPSFYHLSEIVENLLPGQY SEQ ID No 897 KKSYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEEDKLKDWEGGL DEQRLSADSGYIIPLPDIDPVPEEEDLGKRNRHSSQTSEESAIETGSSSS TFIKREDETIEDIDMMDDIGIDSSDLVEDSFL QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRL SEQ ID No 898 QLEKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSII ASCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAE KNSVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM PDPYKSSILSLIKFKENPHLIIMNVSDCIPDAIEVVSKPEGTKIQFLGTRKSL SEQ ID No 899 TETELTKPNYLYLLPTEKNHSGPGPCICFENLTYNQAASDSGSCGHVPV SPKAPSMLGLMTSPENVLKALEKNYMNSLGEIPAGETSLNYVSQLASPM FGDKDSLPTNPVEAPHCSEYKMQMAVSLRLALPPPTENSSLSSITLLDP GEHYC PNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIED SEQ ID No 900 TEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVI YIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDL DKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPP KDEDSPKSNGGGWSFTNFFQNKPND RDVKKGNLPPDYRISLIDIGLVIEYLMGGAYRCNYTRKRFRTLYHNLFGP SEQ ID No 901 KRPKALKLLGMEDDIPLRRGRKTTKKREEEVDIDLDDPEINHFPFPFHEL MVWAVLMKRQKMALFFWQHGEEAMAKALVACKLCKAMAHEASENDM VDDISQELNHNSRDFGQLAVELLDQSYKQDEQLAMKLLTYELKNWSNAT CLQLAVAAKHRDFIAHTCSQMLLTDMWMGRLRMRK KDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSR SEQ ID No 902 KSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS GNANAAKPDLDKVISLKEANVKLRANALIKRGSMYMQQQQPLLSTQDFN SEQ ID No 903 MAADIDPQNADVYHHRGQLKILLDQVEEAVADFDECIRLRPESALAQAQ KCFALYRQAYTGNNSSQIQAAMKGFEEVIKKFPRCAEGYALYAQALTDQ QQFGKADEMYDKCIDLEPDNATTYVHKGLLQLQWKQDLDRGLELISKAI EIDNKCDFAYETMGTIEVQRGNMEKAIDMFNKAINLAKSEMEMAHLYSLC DAAHAQTEVAKKYGLKPPTL ENEAPWVTDKRPPPDWPSKGKIQFNNYQVRYRPELDLVLRGITCDIGSM SEQ ID No 904 EKIGVVGRTGAGKSSLTNCLFRILEAAGGQIIIDGVDIASIGLHDLREKLTII PQDPILFSGSLRMNLDPFNNYSDEEIWKALELAHLKSFVASLQLGLSHEV TEAGGNLSIGQRQLLCLGRALLRKSKILVLDEATAAVDLETDNLIQTTIQN EFAHCTVITIAHRLHTIMDSDKVMVLDNGKIIECGSPEELLQIPGPFYFMA KEAGIENVNSTKF CETLQFLDCICGSTTGGLGLLGLYINEKNVALINQTLESLTEYCQGPCHE SEQ ID No 905 NQNCIATHESNGIDIITALILNDINPLGKKRMDLVLELKNNASKLLLAIMESR HDSENAERILYNMRPKELVEVIKKAYMQGEVEFEDGENGEDGAASPRN VGHNIYILAHQLARHNKELQSMLKPGGQVDGDEALEFYAKHTAQIEIVRL DRTMEQIVFPVPSICEFLTKESKLRIYYTTERDEQGSKINDFFLRSEDLFN EMNWQKKLRAQPVLYWCARNMS CETLQFLDCICGSTTGGLGLLGLYINEKNVALVNQNLESLTEYCQGPCHE SEQ ID No 906 NQTCIATHESNGIDIIIALILNDINPLGKYRMDLVLQLKNNASKLLLAIMESR HDSENAERILFNMRPRELVDVMKNAYNQGLECDHGDDEGGDDGVSPK DVGHNIYILAHQLARHNKLLQQMLKPGSDPDEGDEALKYYANHTAQIEIV RHDRTMEQIVFPVPNICEYLTRESKCRVFNTTERDEQGSKVNDFFQQTE DLYNEMKWQKKIRNNPALFWFSRHIS NNSTVSRTSASKYENMIRYTGSPDSLRSRTPMITPDLESGVKMWHLVKN SEQ ID No 907 HEHGDQKEGDRGSKMVSEIYLTRLLATKGTLQKFVDDLFETIFSTAHRG SALPLAIKYMFDFLDEQADKHGIHDPHVRHTWKSNCLPLRFWVNMIKNP QFVFDIHKNSITDACLSWAQTFMDSCSTSEHRLGKDSPSNKLLYAKDIP SYKNWVERYYSDIGKMPAISDQDMNAYLAEQSRMHMNEFNTMSALSEI FSYVGKYSEEILGPLDHDDQCGKQKLAYKLEQVITLMSLDS CETLQFLDIMCGSTTGGLGLLGLYINEDNVGLVIQTLETLTEYCQGPCHE SEQ ID No 908 NQTCIVTHESNGIDIITALILNDISPLCKYRMDLVLQLKDNASKLLLALMES RHDSENAERILISLRPQELVDVIKKAYLQEEERENSEVSPREVGHNIYILA LQLSRHNKQLQHLLKPVKRIQEEEAEGISSMLSLNNKQLSQMLKSSAPA QEEEEDPLAYYENHTSQIEIVRQDRSMEQIVFPVPGICQFLTEETKHRLF TTTEQDEQGSKVSDFFDQSSFLHNEMEWQRKLRSMPLIYWFSRRMT LADGSFVRCTPSENSDLFYAVPWSCGTLGFLVAAEIRIIPAKKYVKLRFEP SEQ ID No 909 VRGLEAICAKFTHESQRQENHFVEGLLYSLDEAVIMTGVMTDEAEPSKL NSIGNYYKPWFFKHVENYLKTNREGLEYIPLRHYYHRHTRSIFWELQDIIP FGNNPIFRYLFGWMVPPKISLLKLTQGETLRKLYEQHHVVQDMLVPMKC LQQALHTFQNDIHVYPIWLCPFILPSQPGLVHPKGNEAELYIDIGAYGEPR VKHFEARSCMRQLEKFVRSVHGFQMLYADCYMNREEFWEMFDGSLYH KLREKLGCQDAFPEVYDKICKAARH NPEYFSASDMYVPDEWEVPREQISIIRELGQGSFGMVYEGLARGLEAGE SEQ ID No 910 ESTPVALKTVNELASPRECIEFLKEASVMKAFKCHHWRLLGVVSQGQP TLVIMELMTRGDLKSHLRSLRPEAENNPGLPQPALGEMIQMAGEIADGM AYLAANKFVHRDLAARNCMVSQDFTVKIGDFGMTRDVYETDYYRKGGK GLLPVRWMAPESLKDGIFTTHSDVWSFGVVLWEIVTLAEQPYQGLSNEQ VLKFVMDGGVLEELEGCPLQLQELMSRCWQPNPRLRPSFTHILDSIQEE LRPSFRLLSFYYSPECRGARGSLPTTDAEPDSSPTPRDCSPQNGGPGH PAPSALTPKILDLLVHAISINSAYTTKILPPEKEGALPRQVGNKTECALLGF SEQ ID No 911 VLDLKRDFQPVREQIPEDKLYKVYTFNSVRKSMSTVIRMPDGGFRLFSK GASEILLKKCTNILNSNGELRGFRPRDRDDMVRKIIEPMACDGLRTICIAY RDFSAGQEPDWDNENEVVGDLTCIAVVGIEDPVRPEVPEAIRKCQRAGI TVRMVTGDNINTARAIAAKCGIIQPGEDFLCLEGKEFNRRIRNEKGEIEQE RLDKVWPKLRVLARSSPTDKHTLVKGIIDSTTGEQRQVVAVTGDGTNDG PALKKADVGFAMGIAGTDVAKEASDIILTDDNFTSIVKAVMWGRNVYDSI GGDQLNCHFGSILHTTGLQYRDFIHVSFHDKVYELPFLVALDHRKESVVV SEQ ID No 912 AVRGTMSLQDVLTDLSAESEVLDVECEVQDRLAHKGISQAARYVYQRLI NDGILSQAFSIAPEYRLVIVGHSLGGGAAALLATMLRAAYPQVRCYAFSP PRGLWSKALQEYSQSFIVSLVLGKDVIPRLSVTNLEDLKRRILRVVAHCN KPKYKILLHGLWYELFGGNPNNLPTELDGGDQEVLTQPLLGEQSLLTRW SPAYSFSSDSPLDSSPKYPPLYPPGRIIHLQEEGASGRFGCCSAAHYSA KWSHEAEFSKILIGPKMLTDHMPDILMRALDSVVSDRAACVSCPAQGVS SVDVA PYSQRPKAEDMDLEWRQGRMTRIILQDEDVTTKIECDWKRLNSLAHYQ SEQ ID No 913 VTDGSLVALVPKQVSAYNMANSFTFTRSLSRYESLLRTASSPDSLRSRA PMITPDQETGTKLWHLVKNHDHADHREGDRGSKMVSEIYLTRLLATKGT LQKFVDDLFETVFSTAHRGSALPLAIKYMFDFLDEQADQRQISDPDVRHT WKSNCLPLRFWVNVIKNPQFVFDIHKNSITDACLSVVAQTFMDSCSTSE HRLGKDSPSNKLLYAKDIPNYKSWVERYYRDIAKMASISDQDMDAYLVE QSRLHASDFSVLSALNELYFYVTKYRQEILTALDRDASCRKHKLRQKLEQ IISLVSSDS KSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGACTI SEQ ID No 914 GGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKES SCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDE LALDLEDLLSFSYQVAKGMAFLASKNCIHRDLAARNILLTHGRITKICDFG LARDIKNDSNYVVKGNARLPVKWMAPESIFNCVYTFESDVWSYGIFLWE LFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMYDIMKTCWDA DPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSV GSTASSSQPLLVHDDV HVPKSYRRRRRHKRKTGHKEKKEKERISENYSDKSDIENADESSSSILKP SEQ ID No 915 LISPAAERIRFILGEEDDSPAPPQLFTELDELLAVDGQEMEWKETARWIK FEEKVEQGGERWSKPHVATLSLHSLFELRTCMEKGSIMLDREASSLPQL VEMIVDHQIETGLLKPELKDKVTYTLLRKHRHQTKKSNLRSLADIGKTVSS ASRMFTNPDNGSPAMTHRNLTSSSLNDISDKPEKDQLKNKFMKKLPRD AEASNVLVGEVDFLDTPFIAFVRLQQAVMLGALTEVPVPTRFLFILLGPKG KAKSYHEIGRAIATLMSDEVFHDIAYKAKDRHDLIAGIDEFLDEVIVLPPGE WDPAIRIEPPKSLPSSDKRKNMYSGGENVQMNGDTPHDGGHGGGGHG DCEELQRTGRFCGGLIKDIKRKAPFFASDFYDALNIQ WIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGIC SEQ ID No 916 LTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLE DVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIK WMALESILRRRFTHQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLE KGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQR FVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPD PAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEGA GSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVA PLTCSPQPEYVNQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGK NGVVKDVFAFGGAVENPEYLTPQGGAAPQPHPPPAFSPAFDNLYYWD QDPPERGAPPSTFKGTPTAENPEYLGLDVPV IMDPDEVPLDEQCERLPYDASKWEFARERLKLGKSLGRGAFGKVVQAS SEQ ID No 917 AFGIKKSPTCRTVAVKMLKEGATASEYKALMTELKILTHIGHHLNVVNLLG ACTKQGGPLMVIVEYCKYGNLSNYLKSKRDLFFLNKDAALHMEPKKEKM EPGLEQGKKPRLDSVTSSESFASSGFQEDKSLSDVEEEEDSDGFYKEPI TMEDLISYSFQVARGMEFLSSRKCIHRDLAARNILLSENNVVKICDFGLAR DIYKNPDYVRKGDTRLPLKWMAPESIFDKIYSTKSDVWSYGVLLWEIFSL GGSPYPGVQMDEDFCSRLREGMRMRAPEYSTPEIYQIMLDCWHRDPK ERPRFAELVEKLGDLLQANVQQDGKDYIPINAILTGNSGFTYSTPAFSED FFKESISAPKFNSGSSDDVRYVNAFKFMSLERIKTFEELLPNATSMFDDY QGDSSTLLASPMLKRFTWTDSKPKASLKIDLRVTSKSKESGLSDVSRPS FCHSSCGHVSEGKRRFTYDHAELERKIACCSPPPDYNSVVLYSTPPI IMDPGEVPLEEQCEYLSYDASQWEFPRERLHLGRVLGYGAFGKVVEAS SEQ ID No 918 AFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKILIHIGNHLNVVNLLG ACTKPQGPLMVIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRFRA MVELARLDRRRPGSSDRVLFARFSKTEGGARRASPDQEAEDLWLSPLT MEDLVCYSFQVARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLAR DIYKDPDYVRKGSARLPLKWMAPESIFDKVYTTQSDVWSFGVLLWEIFS LGASPYPGVQINEEFCQRLRDGTRMRAPELATPAIRRIMLNCWSGDPKA RPAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQSSEEGSFSQVSTMAL HIAQADAEDSPPSLQRHSLAARYYNWVSFPGCLARGAETRGSSRMKTF EEFPMTPTTYKGSVDNQTDSGMVLASEEFEQIESRHRQESGFSCKGPG QNVAVTRAHPDSQGRRRRPERGARGGQVFYNSEYGELSEPSEEDHCS PSARVTFFTDNSY VMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEAD SEQ ID No 919 AFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLG ACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYV GAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTL EHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDI YKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLG ASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQ RPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPV SCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPE VKVIPDDNQTDSGMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASE GSNQTSGYQSGYHSDDTDTTVYSSEEAELLKLIEIGVQTGSTAQILQPDS GTTLSSPPV FEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEELKEKLRDVMVDR SEQ ID No 920 HKVALGKTLGEGEFGAVMEGQLNQDDSILKVAVKTMKIAICTRSELEDFL SEAVCMKEFDHPNVMRLIGVCFQGSERESFPAPVVILPFMKHGDLHSFL LYSRLGDQPVYLPTQMLVKFMADIASGMEYLSTKRFIHRDLAARNCMLN ENMSVCVADFGLSKKIYNGDYYRQGRIAKMPVKWIAIESLADRVYTSKS DVWSFGVTMWEIATRGQTPYPGVENSEIYDYLRQGNRLKQPADCLDGL YALMSRCWELNPQDRPSFTELREDLENTLKALPPAQEPDEILYVNMDEG GGYPEPPGAAGGADPPTQPDPKDSCSCLTAAEVHPAGRYVLCPSTTPS PAQPADRGSPAAPGQEDGA WVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGV SEQ ID No 921 CLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLE ERRLVHRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPI KWMALECIHYRKFTHQSDVWSYGVTIWELMTFGGKPYDGIPTREIPDLL EKGERLPQPPICTIDVYMVMVKCWMIDADSRPKFKELAAEFSRMARDPQ RYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAEEYLVPQAFNIP PPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYS ADPTVFAPERSPRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKN GDLQALDNPEYHNASNGPPKAEDEYVNEPLYLNTFANTLGKAEYLKNNI LSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQEYSTKYFYKQNGRI RPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV DLSNKINEMKTFNSPNLKDGRFVNPSGQPTPYATTQLIQSNLSNNMNNG SEQ ID No 922 SGDSGEKHWKPLGQQKQEVAPVQYNIVEQNKLNKDYRANDTVPPTIPY NQSYDQNTGGSYNSSDRGSSTSGSQGHKKGARTPKVPKQGGMNWAD LLPPPPAHPPPHSNSEEYNISVDESYDQEMPCPVPPARMYLQQDELEEE EDERGPTPPVRGAASSPAAVSYSHQSTATLTPSPQEELQPMLQDCPEE TGHMQHQPDRRRQPVSPPPPPRPISPPHTYGYISGPLVSDMDTDAPEE EEDEADMEVAKMQTRRLLLRGLEQTPASSVGDLESSVTGSMINGWGSA SEEDNISSGRSSVSSSDGSFFTDADFAQAVAAAAEYAGLKVARRQMQD AAGRRHFHASQCPRPTSPVSTDSNMSAAVMQKTRPAKKLKHQPGHLR RETYTDDLPPPPVPPPAIKSPTAQSKTQLEVRPVVVPKLPSMDARTDRS SDRKGSSYKGREVLDGRQVVDMRTNPGDPREAQEQQNDGKGRGNKA AKRDLPPAKTHLIQEDILPYCRPTFPTSNNPRDPSSSSSMSSRGSGSRQ REQANVGRRNIAEMQVLGGYERGEDNNEELEETES EPQDGCHPGDSVERSVTCLPSASDENENQLDGDGHEHLTSSDSAMGK SEQ ID No 923 PQVSEQDSLNNNESCTLSCEVAAGENLQNTLCEASRDEQAFLGKDKKIP GKRSPRSKKGTAKKIPPGLFSGDIAPLMQEKVLSAVTYAVDDEEAAEVN ANEQPEAPKLVLQSLFSLIRGEVEQLDSRALPLCLHQIAESYFQEEDYEK AMKFIQLERLYHEQLLANLSAIQEQWETKWKTVQPHTVTALRNSEKGFN GEDFERLTKICATHQDPLLSKHKIAAVEKSQERKCSTQLLVSEDPKEGGA TTKESESKTCLGTESSKESQHTVEPLGSSPCCHQMDVQTDSPSLSVTA GKDHMEELLCSAEATLALHTQSSETAGSPSGPDSSEDACEDDSRLQLA QTEACQDVARIEGIAEDPKVFLSSKSKTEPLISPGCDRIPPALISEGKYSQ AQRKELRLPLRDASEALPTDQLENNELNELQQPDLTDSDGKSPQAQAD SDGSENVLCGNNQISDLGILLPEVCMAPEEKGDKDDQLNKETEDYLNSL LEGCLKDTEDSLSYEDNQDDDSDLLQDLSPEEASYSLQENLPSDESCLS LDDLAKRIEIAEVVPTEGLVSILKKRNDTVGDHPAQMQHKPSKRRVRFQE IDDSLDQDEVGGGS SKNIPTTKDVEPLLEIDGDIRNFEVFLSSRTPVLVARDVKVFLPCTVNLDP SEQ ID No 924 KLREIIADVRAAREQISIGGLAYPPLPLHEGPPRAPSGYSQPPSVCSSTSF NGPFAGGVVSPQPHSSYYSGMTGPQHPFYNRPFFAPYLYTPRYYPGG SQHLISRPSVKTSLPRDQNNGLEVIKEDAAEGLSSPTDSSRGSGPAPGP VVLLNSLNVDAVCEKLKQIEGLDQSMLPQYCTTIKKANINGRVLAQCNID ELKKEMNMNFGDWHLFRSTVLEMRNAESHVVPEDPRFLSESSSGPAPH GEPARRASHNELPHTELSSQTPYTLNFSFEELNTLGLDEGAPRHSNLSW QSQTRRTPSLSSLNSQDSSIEISKLTDKVQAEYRDAYREYIAQMSQLEG GPGSTTISGRSSPHSTYYMGQSSSGGSIHSNLEQEKGKDSEPKPDDGR KSFLMKRGDVIDYSSSGVSTNDASPLDPITEEDEKSDQSGSKLLPGKKS SERSSLFQTDLKLKGSGLRYQKLPSDEDESGTEESDNTPLLKDDKDRKA EGKVERVPKSPEHSAEPIRTFIKAKEYLSDALLDKKDSSDSGVRSSESSP NHSLHNEVADDSQLEKANLIELEDDSHSGKRGIPHSLSGLQDPIIARMSIC SEDKKSPSECSLIASSPEENWPACQKAYNLNRTPSTVTLNNNSAPANRA NQNFDEMEGIRETSQVILRPSSSPNPTTIQNENLKSMTHKRSQRSSYTR LSKDPPELHAAASSESTGFGEERESIL WSLGVTLWELFDNAAQPYSNLSNLDVLNQVIRERDTKLPKPQLEQPYSD SEQ ID No 925 RWYEVLQFCWLSPEKRPAAEDVHRLLTYLRLQSQRDSEVDFEQQWNA LKPNTNSRDSSNNAAFPILDHFARDRLGREMEEVLTVTETSQGLSFEYV WEAAKHDHFDERSRGHLDEGLSYTSIFYPVEVFESSLSDPGPGKQDDS GQDVPLRVPGVVPVFDAHNLSVGSDYYIQLEEKSGSNLELDYPPALLTT DMDNPERTGPELSQLTALRSVELEESSTDEDFFQSSTDPKDSSLPGDLH VTSGPESPFNNIFNDVDKSEDLPSHQKIFDLMELNGVQADFKPATLSSSL DNPKESVITGHFEKEKPRKIFDSEPLCLSDNLMHQDNFDPLNVQELSENF LFLQEKNLLKGSLSSKEHINDLQTELKNAGFTEAMLETSCRNSLDTELQF AENKPGLSLLQENVSTKGDDTDVMLTGDTLSTSLQSSPEVQVPPTSFET EETPRRVPPDSLPTQGETQPTCLDVIVPEDCLHQDISPDAVTVPVEILST DARTHSLDNRSQDSPGESEETLRLTESDSVLADDILASRVSVGSSLPEL GQELHNKPFSEDHHSHRRLEKNLEAVETLNQLNSKDAAKEAGLVSALSS DSTSQDSLLEDSLSAPFPASEPSLETPDSLESVDVHEALLDSLGSHTPQK LVPPDKPADSGYETENLESPEWTLHPAPEGTADSEPATTGDGGHSGLP PNPVIVISDAGDGHRGTEVTPETFTAGSQGSYRDSAYFSDNDSEPEKRS EEVPGTSPSALVLVQEQPLPEPVLPEQSPAAQDSCLEARKSQPDESCLS ALHNSSDLELRATPEPAQTGVPQQVHPTEDEASSPWSVLNAELSSGDD FETQDDRPCTLASTGTNTNELLAYTNSALDKSLSSHSEGPKLKEPDIEGK YLGKLGVSGMLDLSEDGMDADEEDENSDDSDEDLRAFNLHSLSSESED ETEHPVPIILSNEDGRHLRSLLKPTAANAPDPLPEDWKKEKKAVTFFDDV TVYLFDQETPTKELGPCGGEACGPDLSGPAPASGSPYLSRCINSESSTD EEGGGFEWDDDFSPDPFMSKTTSNLLSSKPSLQTSKYFSPPPPARSTE QSWPHSAPYSRFSISPANIASFSLTHLTDSDIEQGGSSEDGEKD

In some embodiments, variants of the sequence ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% amino acid sequence identity with said sequence.

In some embodiments, variants of the sequence ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) have at least 95% amino acid sequence identity with said sequence.

In some embodiments, variants of the sequence ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) have at least 99% amino acid sequence identity with said sequence.

In some embodiments, variants of the sequence ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) have substantially the same activity as the non-variant sequence. In some embodiments, substantially the same activity refers to at least 80%, 85%, 90%, 95% of the activity of the non-variant sequence.

In some embodiments, substantially the same activity refers to at least 80%, 85%, 90%, 95% of the activity of the non-variant sequence as measured by monitoring the luciferase activity in reporter cells comprising a P-CAR and an N-CAR comprising the intracellular domain to be tested and incorporating inducible NFAT- or NfkB-regulated luciferase expression, such as for example as disclosed in Example 3 below.

Transmembrane Domain of the N-CAR

With respect to the transmembrane domain, in various embodiments, a N-CAR can be designed to comprise a transmembrane domain that is attached to the extracellular domain of the N-CAR. A transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, e.g., one or more amino acid associated with the extracellular region of the protein from which the transmembrane was derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the extracellular region) and/or one or more additional amino acids associated with the intracellular region of the protein from which the transmembrane protein is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the intracellular region). In one aspect, the transmembrane domain is one that is associated with one of the other domains of the N-CAR. In some instances, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins, e.g., to minimize interactions with other members of the receptor complex. In one aspect, the transmembrane domain is capable of homodimerization with another CAR on the CAR T-cell surface. In a different aspect the amino acid sequence of the transmembrane domain may be modified or substituted so as to minimize interactions with the binding domains of the native binding partner present in the same CAR T-Cell.

The transmembrane domain may be derived either from a natural or from a recombinant source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In one aspect the transmembrane domain is capable of signaling to the intracellular domain(s) whenever the N-CAR has bound to a target. A transmembrane domain of particular use in this invention may include at least the transmembrane region(s) of e.g., the alpha, beta or zeta chain of the T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3 epsilon, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154.

In some embodiment, the transmembrane domain of the N-CAR includes at least the transmembrane region(s) of PD-1 or CD28alpha.

In some embodiments, the transmembrane domain can be attached to the extracellular domain of the N-CAR, via a hinge, e.g., a hinge from a human protein. For example, in one embodiment, the hinge can be a human Ig (immunoglobulin) hinge, e.g., a PD-1 hinge, an IgG4 hinge, or a CD8alpha hinge.

In some embodiments, the transmembrane domain may be recombinant, in which case it will comprise predominantly hydrophobic residues such as leucine and valine. In one aspect a triplet of phenylalanine, tryptophan and valine can be found at each end of a recombinant transmembrane domain.

Optionally, a short oligo- or polypeptide linker, between 2 and 10 amino acids in length may form the linkage between the transmembrane domain and the cytoplasmic region of the N-CAR. A glycine-serine doublet provides a particularly suitable linker. For example, in one aspect, the linker comprises the amino acid sequence of GGGGSGGGGS. In some embodiments, the linker is encoded by a nucleotide sequence of GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC.

Extracellular domain of the N-CAR

The antigen binding domain can be any domain that binds to the off-tissue antigen including but not limited to a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including but not limited to a single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of camelid derived nanobody, and to an alternative scaffold known in the art to function as antigen binding domain, such as a recombinant fibronectin domain, and the like. In some instances, it is beneficial for the antigen binding domain to be derived from the same species in which the N-CAR will ultimately be used in. For example, for use in humans, it may be beneficial for the antigen binding domain of the N-CAR to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment.

A humanized antibody can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated herein in its entirety by reference), veneering or resurfacing (see, e.g., European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering, 7(6):805-814; and Roguska et al., 1994, PNAS, 91:969-973, each of which is incorporated herein by its entirety by reference), chain shuffling (see, e.g., U.S. Pat. No. 5,565,332, which is incorporated herein in its entirety by reference), and techniques disclosed in, e.g., U.S. Patent Application Publication No. US2005/0042664, U.S. Patent Application Publication No. US2005/0048617, U.S. Pat. No. 6,407,213, U.S. Pat. No. 5,766,886, International Publication No. WO 9317105, Tan et al., J. Immunol., 169: 1119-25 (2002), Caldas et al., Protein Eng., 13(5):353-60 (2000), Morea et al., Methods, 20(3):267-79 (2000), Baca et al., J. Biol. Chem., 272(16): 10678-84 (1997), Roguska et al., Protein Eng., 9(10):895-904 (1996), Couto et al., Cancer Res., 55 (23 Supp):5973s-5977s (1995), Couto et al., Cancer Res., 55(8): 1717-22 (1995), Sandhu J S, Gene, 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol., 235(3):959- 73 (1994), each of which is incorporated herein in its entirety by reference. Often, framework residues in the framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, for example improve, antigen binding. These framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, which are incorporated herein by reference in their entireties.).

In some aspects, the portion of an N-CAR that comprises an antibody fragment is humanized with retention of high affinity for the target antigen and other favorable biological properties. According to one aspect of the invention, humanized antibodies and antibody fragments are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, e.g., the analysis of residues that influence the ability of the candidate immunoglobulin to bind the target antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody or antibody fragment characteristic, such as increased affinity for the target antigen, is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding.

In some embodiments, the antibody binding domain is a fragment, e.g., a single chain variable fragment (scFv). In some embodiments, the antibody binding domain is a Fv, a Fab, a (Fab′)2, or a bi-functional (e.g. bi-specific) hybrid antibody (e.g., Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)). In some embodiments, the antigen binding domain of the N-CAR of the invention binds an off-tissue antigen with wild-type or enhanced affinity.

In some instances, scFvs can be prepared according to method known in the art (see, for example, Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). ScFv molecules can be produced by linking VH and VL regions together using flexible polypeptide linkers. The scFv molecules comprise a linker (e.g., a Ser-Gly linker) with an optimized length and/or amino acid composition. The linker length can greatly affect how the variable regions of a scFv fold and interact. In fact, if a short polypeptide linker is employed (e.g., between 5-10 amino acids) intrachain folding is prevented. Interchain folding is also required to bring the two variable regions together to form a functional epitope binding site. For examples of linker orientation and size see, e.g., Hollinger et al. 1993 Proc Natl Acad. Sci. U.S.A. 90:6444-6448, U.S. Patent Application Publication Nos. 2005/0100543, 2005/0175606, 2007/0014794, and PCT publication Nos. WO2006/020258 and WO2007/024715, is incorporated herein by reference.

An scFv can comprise a linker of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more amino acid residues between its VL and VH regions. The linker sequence may comprise any naturally occurring amino acid. In some embodiments, the linker sequence comprises amino acids glycine and serine. In another embodiment, the linker sequence comprises sets of glycine and serine repeats such as (Gly₄Ser)_(n), where n is a positive integer equal to or greater than 1. In one embodiment, the linker can be (Gly₄Ser)₄ or (Gly₄Ser)₃. Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies.

In a preferred embodiment, the antigen binding domain of the N-CAR comprises an scFv.

The off-tissue antigen recognized by the antigen binding domain of the N-CAR is preferably an antigen that is not present or present at low level on the tumour cells targeted by the P-CAR.

The below table provide examples of combinations of N-CAR and P-CAR antigens.

P-CAR Antigen N-CAR Antigen CD33 Antigens specifically expressed in dendritic cells and/or haema- topoetic stem cells such as ITGAX, CD1E, CD34, CD1C, CD123, CD141 FLT3 Antigens specifically expressed in haematopoetic stem cells such as CD34 or specifically expressed in Brain cerebellum such as ZP2, GABRA6, CRTAM, GRM4, MDGA1 MSLN Antigens specifically expressed in lung such as SFTPC, ROS1, SLC6A4, AGTR2 MUC16 Antigens specifically expressed in salivary gland such as LRRC26, HTR3A, TMEM211, MRGPRX3 MUC17 Antigens specifically expressed in colon & small intestine such as MEP1B, TMIGD1, CEACAM20, ALPI

N-CAR antigens could also include antigens that are independent of the antigen that the P-CAR is targeting and that are down-regulated in tumor of interest, but present in all normal tissues of concern. Examples of such antigens for pancreatic ductal adenocarcinoma are TMPRSS11B, CYP17A1 and ATP4B and examples of such antigens for kidney clear cell carcinoma are GP2, MUC21, CLCA4 and SLC27A6.

The present invention encompasses a recombinant DNA construct comprising sequences encoding an N-CAR as defined above, wherein the N-CAR comprises an extracellular domain such as an antibody fragment that binds specifically to an off-tumor antigen, and wherein the sequence of the extracellular domain is contiguous with and in the same reading frame as a nucleic acid sequence encoding a transmembrane domain and an intracellular domain. In some embodiments, an exemplary N-CAR construct comprises an optional leader sequence, an extracellular off-tissue antigen binding domain, a hinge, a transmembrane domain, and an intracellular inhibitory signaling domain.

The present invention includes retroviral and lentiviral vector constructs expressing an N-CAR that can be directly transduced into a cell.

The present invention also includes an RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection involves in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3′ and 5′ untranslated sequence (“UTR”), a 5′ cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length. RNA so produced can efficiently transfect different kinds of cells. In one embodiment, the template includes sequences for the N-CAR. In an embodiment, an RNA N-CAR vector is transduced into a T-cell by electroporation.

In some embodiments, the invention relates to an isolated immune cell comprising an N-CAR as defined herein. In some embodiments, the invention further relates to immune cells comprising an N-CAR as defined herein and a P-CAR. In some embodiments, said immune cell is a T-cell. In some embodiments, said T-cell is a human T-cell.

The term “positive signaling Chimeric Antigen Receptor” or alternatively a “P-CAR” refers to a recombinant polypeptide construct comprising at least an extracellular domain comprising an antigen binding domain, a transmembrane domain and an intracellular domain (also referred to herein as a “cytoplasmic signaling domain” or “an intracellular signaling domain”) comprising a functional signaling domain derived from a stimulatory molecule as defined below. In some embodiments, the stimulatory molecule is the zeta chain associated with the T-cell receptor complex. In some embodiments, the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below. In some embodiments, the costimulatory molecule is chosen from 4-1BB (i.e., CD137), CD27 and/or CD28. In some embodiments, the P-CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a stimulatory molecule. In some embodiments, the P-CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a co- stimulatory molecule and a functional signaling domain derived from a stimulatory molecule. In some embodiments, the P-CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising two functional signaling domains derived from one or more co- stimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule. In some embodiments, the P-CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising at least two functional signaling domains derived from one or more co-stimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule. In some embodiments the P-CAR comprises an optional leader sequence at the amino-terminus (N-ter) of the P-CAR fusion protein. In some embodiments, the P-CAR further comprises a leader sequence at the N-terminus of the extracellular antigen recognition domain, wherein the leader sequence is optionally cleaved from the antigen recognition domain (e.g., aa scFv) during cellular processing and localization of the P-CAR to the cellular membrane.

The extracellular portion of a P-CAR comprising an antibody or antibody fragment thereof may exist in a variety of forms where the antigen binding domain is expressed as part of a contiguous polypeptide chain including, for example, a single domain antibody fragment (sdAb), a single chain antibody (scFv) and a humanized antibody (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al, 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).

The term “stimulatory molecule,” refers to a molecule expressed by a T-cell that provides the positive cytoplasmic signaling sequence(s) that regulate positive activation of the TCR complex in a stimulatory way for at least some aspect of the T-cell signaling pathway. In some embodiments, the positive signal is initiated by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, and which leads to mediation of a T-cell response, including, but not limited to, proliferation, activation, differentiation, and the like. A positive cytoplasmic signaling sequence (also referred to as a “positive signaling domain” or positive intracellular signaling domain) that acts in a stimulatory manner may contain a signaling motif which is known as immunoreceptor tyrosine- based activation motif or ITAM. Examples of an ITAM containing positive cytoplasmic signaling sequence includes, but is not limited to, those derived from TCR zeta (or CD3zeta), FcR gamma, FcR beta, CD3 gamma, CD3 delta , CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (also known as “ICOS”) and CD66d.

In some aspect, the intracellular signaling domain of the P-CAR can comprise a positive intracellular signaling domain. The positive intracellular signaling domain generates a signal that promotes an immune effector function of the P-CAR containing cell, e.g., a P-CAR T-cell. Examples of immune effector function, e.g., in a P-CAR T-cell, include cytolytic activity and helper activity, including the secretion of cytokines.

The term “costimulatory molecule” refers to the cognate binding partner on a T-cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T-cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an efficient immune response. Costimulatory molecules include, but are not limited to an MHC class I molecule, BTLA and a Toll ligand receptor, as well as OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18) and 4-IBB (CD137).

A costimulatory intracellular signaling domain can be the intracellular portion of a costimulatory molecule. A costimulatory molecule can be represented in the following protein families: TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), and activating NK cell receptors. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and a ligand that specifically binds with CD83, and the like.

P-CARs and immune cells comprising them have been extensively disclosed and can be prepared by the skilled person according to known methods. For example, methodologies to prepare P-CAR and cells comprising such P-CARs are disclosed in U.S. Pat. No. 7,446,190, WO2008/121420, U.S. Pat. No. 8,252,592, US20140024809, WO2012/079000, WO2014153270, WO2012/099973, WO2014/011988, WO2014/011987, WO2013/067492, WO2013/070468, WO2013/040557, WO2013/126712, WO2013/126729, WO 2013/126726, WO2013/126733, U.S. Pat. No. 8,399,645, US20130266551, US20140023674, WO2014039523, U.S. Pat. No. 7,514,537, U.S. Pat. No. 8,324,353, WO2010/025177, U.S. Pat. No. 7,446,179, WO2010/025177, WO2012/031744, WO2012/136231A1, WO2012/050374A2, WO2013074916, WO2009/091826A3, WO2013/176915 or WO/2013/059593 which are all incorporated herein in their entirety by reference. Immune cells comprising a P-CAR and a N-CAR can be prepared by the skilled person according to the methodologies disclosed in the above mentioned references. In a preferred embodiment, immune cells comprising a P-CAR and a N-CAR can be prepared by the skilled person according to the methodologies disclosed in WO2013/176915.

In some embodiments, the method of engineering T-cells of invention can comprise:

(a) modifying T-cells by inactivating at least:

-   -   A first gene expressing a target for an immunosuppressive agent,         and     -   A second gene encoding a component of the T-cell receptor (TCR)

(b) Expanding said cells, optionally in presence of said immunosuppressive agent.

An immunosuppressive agent is an agent that suppresses immune function by one of several mechanisms of action. In other words, an immunosuppressive agent is a role played by a compound which is exhibited by a capability to diminish the extent and/or voracity of an immune response. As non-limiting example, an immunosuppressive agent can be a calcineurin inhibitor, a target of rapamycin, an interleukin-2 u-chain blocker, an inhibitor of inosine monophosphate dehydrogenase, an inhibitor of dihydrofolic acid reductase, a corticosteroid or an immunosuppressive antimetabolite.

In a particular embodiment, the genetic modification step of the method relies on the inactivation of one gene selected from the group consisting of CD52, GR, TCR alpha and TCR beta. In another embodiment, the genetic modification step of the method relies on the inactivation of two genes selected from the group consisting of CD52 and GR, CD52 and TCR alpha, CDR52 and TCR beta, GR and TCR alpha, GR and TCR beta, TCR alpha and TCR beta. In another embodiment, the genetic modification step of the method relies on the inactivation of more than two genes. The genetic modification is preferably operated ex-vivo.

In some embodiments, the method of engineering T-cells of invention can comprise

(a) Providing a T-cell, preferably from a cell culture or from a blood sample;

(b) Selecting a gene in said T-cell expressing a target for an immunosuppressive agent;

(c) Transforming said T cell with nucleic acid encoding a rare-cutting endonuclease able to selectively inactivate by DNA cleavage, preferably by double-strand break respectively: said gene encoding a target for said immunosuppressive agent, and at least one gene encoding a component of the T-cell receptor (TCR);

(d) Expressing said rare-cutting endonucleases into said T-cells;

(e) Sorting the transformed T-cells, which do not express TCR on their cell surface;

(f) Expanding said cells, optionally in presence of said immunosuppressive agent.

In some embodiment, the method to engineer cell of the invention further comprises one or more additional genomic modification step. By additional genomic modification step, can be intended the introduction into cells to engineer of one or more protein of interest. Said protein of interest can be a P-CAR and/or an N-CAR.

In some embodiment the P-CAR is a Multi-chain Chimeric Antigen Receptor particularly adapted to the production and expansion of engineered T-cells, the multi-chain CAR comprising at least two of the following components:

a) one polypeptide comprising the transmembrane domain of FcsRl alpha chain and an extracellular ligand-binding domain,

b) one polypeptide comprising a part of N- and C- terminal cytoplasmic tail and the transmembrane domain of FccRl beta chain and/or

c) two polypeptide s comprising each a part of intracytoplasmic tail and the transmembrane domain of FccRl gamma chain, whereby different polypeptides multimerize together spontaneously to form dimeric, trimeric or tetrameric CAR.

Example of tetrameric P-CARs are illustrated in FIG. 3 of WO2013176915 and different versions of multichain P-CARs are represented in FIG. 4 of WO2013176915. Such P-CAR can be expressed in a T-Cell obtained using the above disclosed method together with a N-CAR according to the present disclosure to obtain a T-cell according to the invention.

In some embodiment the invention relates to an immune cell comprising a N-CAR as defined herein and a P-CAR as defined in any of U.S. Pat. No. 7,446,190, WO2008/121420, U.S. Pat. No. 8,252,592, US20140024809, WO2012/079000, WO2014153270, WO2012/099973, WO2014/011988, WO2014/011987, WO2013/067492, WO2013/070468, WO2013/040557, WO2013/126712, WO2013/126729, WO 2013/126726, WO2013/126733, U.S. Pat. No. 8,399,645, US20130266551, US20140023674, WO2014039523, U.S. Pat. No. 7,514,537, U.S. Pat. No. 8,324,353, WO2010/025177, U.S. Pat. No. 7,446,179, WO2010/025177, WO2012/031744, WO2012/136231A1, WO2012/050374A2, WO2013074916, WO/2009/091826A3, WO2013/176915 or WO/2013/059593.

In some embodiments, the immune cell comprises an N-CAR as defined herein and a multi-chain P-CAR as defined in WO2014/039523.

In some embodiments, the immune cell of the invention is activated when the P-CAR antigen binding domain binds to its antigen. In some embodiments, such activation is reduced when the N-CAR antigen binding domain binds to its antigen. In some embodiments such reduction of activation is increased, preferably by at least 5%, 10%, 15%, 20% or 30% in an immune cell comprising an N-CAR according to the invention as compared to the same immune cell comprising an N-CAR comprising the full intracellular domain of PD-1. In some embodiments such reduction of activation is increased, preferably by at least 5%, 10%, 15%, 20% or 30% in an immune cell comprising an N-CAR according to the invention as compared to the same immune cell comprising an N-CAR comprising the full intracellular domain of CTLA-4.

In some embodiments, the activation is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% when the N-CAR and P-CAR antigen binding domains both binds to their respective antigens as compared to when only the CAR antigen binding domain binds to its antigen.

In some embodiments, the level of activation of the immune cell is measured by determining cytokine production. In some embodiments, the level of activation of the immune cell is measured by monitoring IFNgamma production by ELISA and/or FACS and/or luminex assay. In some embodiments, the level of activation of the immune cell is measured by monitoring TNFalpha production by ELISA and/or luminex assay.

In some embodiments, the level of activation of the immune cell is measured by monitoring degranulation, for example by measuring CD107a levels by FACS.

In some embodiments, the level of activation of the immune cell is measured by monitoring the ability of the immune cell to kill target cells.

In some embodiments, the level of activation of the immune cell is measured by monitoring the luciferase activity in reporter cells incorporating inducible NFAT- or NfkB-regulated luciferase expression, such as for example as disclosed in Example 3 below.

In some embodiments, the negative signal of the N-CAR is short-termed and reversible to ensure that the immune cells comprising a P-CAR and an N-CAR according to the invention may be activated when it encounters only P-CAR antigen, despite prior inactivation in a off-tissue setting that has both P-CAR and N-CAR antigens.

EXAMPLES Example 1 Identification of Inhibitory Domains to be used in N-CARs

There are several receptors, i.e. CTLA-4, PD-1, BTLA, TIM-3, LAG3 that are known to provide a negative signal to attenuate or abrogate T-cell signaling. The intracellular signaling components of PD-1 were studied to identify motifs that may be responsible for its activity. PD-1 contains both an immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) and data suggests that the ITSM domain plays a significant role in recruiting phosphatases (i.e. SHP2) that enable inactivation of upstream signaling components, like CD3zeta (see Riley J L., Immunol Rev. 2009 May; 229(1):114-25; or Yokosuka T et al., J Exp Med. 2012 Jun. 4; 209(6):1201-17). Other receptors and molecules with ITSMs were identified and analyzed to help understand the functional role of this sequence motif with the intention to utilize it in providing a negative signal that attenuates or abrogates T-cell activation caused by engagement of the P-CAR. Protein sequences were downloaded from swissprot database restricting to sequences that were annotated as being cytoplasmic. Each of these cytoplasmic sequences was searched for the patterns of interest (ITIM motif, ITSM motif or ITIM and ITSM motif).

Example 2 Design of N-CARs

N-CARs comprising at least one ITSM, alone or in combination with one or more ITIMs or other inhibitory domain such as those of TIM-3, LAG-3 or CTLA4 are prepared in an effort to generate effective NOT gates.

In particular, the following N-CARs are prepared:

-   -   N-CARs comprising multiple tandems PD-1 ITIM-ITSM;     -   N-CARs comprising multiple tandems PD-1 ITSM;     -   N-CARs comprising single or multiple non-PD1 natural ITSM or         ITIM-ITSM;     -   N-CARs comprising synthetic ITSM or ITIM-ITSM;     -   N-CARS comprising at least one ITSM and signaling domains from         other inhibitory receptors such as TIM-3, LAG-3 or CTLA4.

Example 3 Activity of T-Cells Comprising a P-CAR and a N-CAR in Immortalized Human T-Cells

An experimental model is used to test the N-CARs designed according to Example 2. The model consists of a positive signaling CAR (P-CAR) construct containing from the N-terminus, a signaling domain or secretory signal domain (e.g. CD8 secretory signal sequence), anti-CD-19 single-chain antibody, hinge (e.g. CD8alpha), transmembrane (e.g CD8alpha), and positive intracellular signaling domains (e.g. 41BB and CD3zeta). The P-CAR is followed by or preceded by a fluorescent marker (e.g. EGFP) or antibiotic resistance gene separated from the P-CAR by either a P2A or IRES (see for example Table 9).

This construct is constructed using standard molecular biology methods and transduced into T-cell receptor (TCR) negative or an NFAT- or NfkB-regulated luciferase reporter Jurkat cell-line. These cells are purified using bulk FACS sorting using the fluorescent marker or by selection in the appropriate antibiotic followed by flow cytometry to confirm surface CAR expression, and tested for activity against differentially expressing CD19 cell-lines to establish activation, proliferation, and cytokine release, and degranulation/cytotoxicity thresholds. Once an appropriate P-CAR cell line has been identified, these cells are transduced with a plasmid containing the negative signaling CAR (N-CAR) construct containing from the N-terminus, a signaling domain (e.g. CD8 secretory signal sequence), anti-PSMA single-chain antibody, hinge (e.g. truncated PD-1 extracellular domain), transmembrane (e.g. PD-1), and negative intracellular signaling domains to be evaluated (native or modified ITSMs optionally in combination with ITIMs or other inhibitory signaling domains) followed by or preceded by a fluorescent marker (e.g. mCherry) or antibiotic-resistance gene separated from the N-CAR by either a P2A or IRES. Multiple versions of these N-CAR constructs are constructed, using standard site-directed and cassette mutagenesis. The T-cells comprising a P-CAR and a N-CAR (also named P-CAR⁺/N-CAR⁺ T-cells or NOT GATE CAR T-Cells) are purified by bulk FACS sorting on both fluorescent markers (e.g. EGFP and mCherry) or by sequential selection in appropriate antibiotics followed by dual-color flow cytometry to detect surface expression of both CARs, and tested first for retention of P-CAR activity on CD19 expressing cells and then the potency of negative signal on cells expressing both CD19 and PSMA. The N-CAR candidates are characterized by their ability to attenuate positive signal from P-CAR on varying levels of both the P-CAR and N-CAR antigens by monitoring NFAT- or NfkB-regulated luciferase reporter activity, cytokine production (IFNgamma by ELISA/FACS), degranulation (CD107a levels) and killing of target cells (by FACS). Reversibility and the kinetics of reversibility of the N-CAR signal are tested by first incubating the P-CAR⁺/N-CAR⁺ T-cells with cells expressing both CD19 and PSMA, purifying them followed by incubation with CD19 cells.

The cytokine production and cytotoxicity of these cells are compared to cells that were directly incubated with CD19 cells.

Experiment and Results

Jurkat cells (clone E6-1 ATCC# TIB-152) were maintained at a density of 0.4-2×10⁶ cells/mL in RPMI 1640 (Life Technologies) containing 10% fetal bovine serum (hyclone), 1mM sodium pyruvate, 1×glutaMAX, lx nonessential amino acids (Mediatech), and 25mM HEPES buffer.

293T cells (clone HEK-293T/17, ATCC CRL-11268) were maintained subconfluently in DMEM containing 4.5 g/L glucose, 10% fetal bovine serum, 1mM sodium pyruvate, 1 x glutaMAX, lx nonessential amino acids, and 25mM HEPES.

Lentiviral particles (LV) were produced by transient transfection of sub-confluent 293T cells in 6-well plates with a transfer vector (pLVX) encoding the CAR or protein of interest, an HIV- 1 gag pol packaging plasmid (psPAX2), and a VSV-G expression plasmid (pMD2.G) at a 4:3:1 ratio, using Lipofectamine 2000 (Invitrogen). The following day the media was replaced, and 48 h after transfection the LV was harvested and filtered through a 0.45 um Millex-HV syringe filter (Millipore). Fresh LV supernatant was used immediately to transduce sub- confluent Jurkat or 293T cells by diluting LV sup in an equal volume of cell culture medium.

Artificial antigen-presenting cells (AAPCs) were prepared by sequential LV transduction of 293T cells. Subconfluent 293T cells were transfected with pLVX expression constructs encoding either codon-optimized full-length human CD19 (NP_001171569), full-length human PSMA (NP_004467), or empty vector. The pLVX vectors comprised a puromycin-resistance gene followed by a P2A sequence and the target antigen. Transduced 293Ts were subsequently selected in puromycin-containing media, and maintained as pools of expressing clones. Surface antigen expression was determined by flow cytometry, using APC-conjugated goat F(ab′)₂-anti-human PSMA (clone LN1-17, BioLegend cat #342504) or BV421-conjugated mouse-anti-human CD19 (clone H1B19, BD Biosciences cat #562440). Cells were sorted by FACS into populations of CD19 low-expressing or high-expressing clones, PSMA low-expressing or high-expressing clones, and dual CD19 low/PSMA high-expressers or dual CD19 high/PSMA high-expressers.

For determination of T cell activation, a luciferase reporter assay was established in Jurkat cells. Jurkat cells were transduced to stably express a firefly luciferase gene under the control of a minimal (m)CMV promoter and tandem repeats of either the NFKB or NFAT transcriptional response element (TRE) [(Qiagen Cignal Lentivirus]. Transcription factors recognizing these TREs play important roles in T cell signal transduction pathways and are integral in the transcriptional regulation of cytokine genes and other genes critical for the immune response. Upon T cell receptor activation, luciferase reporter activity is modulated and can be measured by quantitative luminometry.

Reporter Jurkat cells (either NFAT-Luc or NFkB-Luc) were subsequently transduced to stably express different combinations of P- and N-CARs. pLVX-CAR encoding constructs comprised an antibiotic resistance gene (puromycin resistance for P-CARS and blasticidin resistance for N-CARs) followed by a P2A sequence and the P- or N-CAR.

In particular, N-FAT-Luc and NFkB-Luc Jurkat cells expressing P-CAR1 or P-CAR2 and an N-CAR comprising an intracellular domain selected from the sequences listed in Table 10 were prepared.

P-CAR1 comprises a ScFv from anti-CD19 antibody FMC63 (see Nicholson et al, (1997), Mol. Immunol. 34: 1157-1165), a CD8 alpha hinge and transmembrane domain, and an intracellular domain comprising a 4-1BB and CD3zeta intracellular signaling domains.

P-CAR2 comprises a ScFv from anti-CD19 antibody SJ25C1 (see US2013063097), a CD28 hinge and transmembrane domain, and an intracellular domain comprising a CD28 and CD3zeta intracellular signaling domains.

The specific sequences of P-CAR1 and P-CAR2 are listed in Table 9.

TABLE 9 P-CAR1 MALPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLN (SEQ ID WYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFC No 2019) QQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQS LSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIK DNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSTTT PAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC ELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKP RRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT YDALHMQALPPR P-CAR2 MALPVTALLLPLALLLHAEVKLQQSGAELVRPGSSVKISCKASGYAFSSYWMN (SEQ ID VVVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGL No 2020) TSEDSAVYFCARKTISSVVDFYFDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIELTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSAT YRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFCQQYNRYPYTSGGGTKL EIKRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVG GVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPR DFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR

The tested N-CARs comprise an amino acid sequence of SEQ ID No 1999 (ScFv from the anti-PSMA antibody J591 (see WO2004/098535), PD1 hinge and transmembrane domain) and an intracellular domain selected from the sequences listed in Table 10. A CAR comprising only SEQ ID No 1999 (no inhibitory intracellular domain) was used as control (APD1).

TABLE 10 N-CAR NAME Intracelullar domain PD1 CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID No 2000) BTLA RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDND PDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEAPT EYASICVRS (SEQ ID No 2001) CD244 WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMIQ SQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNSTIYEVIGKSQPKAQ NPARLSRKELENFDVYS (SEQ ID No 2002) PD1-CTLA4 CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPLAVS LSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN (SEQ ID No 2003) PD1-LAG3 CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPLHL WRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPE QL (SEQ ID No 2004) PD1-PD1 CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPLCS RAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVP EQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID No 2005) PD1-TIM3 CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPLFK WYSHSKEKIQNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPN EYYCYVSSRQQPSQPLGCRFAMP (SEQ ID No 2006) CD300LF WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSS AQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGR GPEEPTEYSTISRP (SEQ ID No 2007) LY9 KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSATIY CSIRKPQVVPPPQQNDLEIPESPTYENFT (SEQ ID No 2008) PECAM KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDV RNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKA VPDAVESRYSRTEGSLDGT (SEQ ID No 2009) SIGLEC9 VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPP PASARSSVGEGELQYASLSFQMVKPWDSRGQEATDTEYSEIKIHR (SEQ ID No 2010) SIRPA RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQAAE PNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYA SVQVPRK (SEQ ID No 2011) PD1-L2-ITSM CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQTEYATIDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGS ADGPRSAQPLRPEDGHCSWPL (SEQ ID No 2012) PD1-L2-ITSM- CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC L2-ITSM VPEQTEYATIDFQWREKTPEPPVPCVPEQTEYATIDFQWREKTPEPPVPCV PEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID No 2013) PD1 (ITSM mut CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC 1) VPEQTEYSEIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID No 2014) PD1 (ITSM mut CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC 2) VPEQTEYSEVVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID No 2015) PD1 (ITSM CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC mut3) VPEQTEYASIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID No 2016) PD1-KIR2DL2 CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPLHR WCSNKKNAAVMDQESAGNRTANSEDSDEQDPQEVTYTQLNHCVFTQRKI TRPSQRPKTPPTDIIVYAELPNAESRSKVVSCP (SEQ ID No 2017)

Three days after transduction, Jurkat cells were placed into antibiotic selection media to select for pools of stable CAR-expressing clones.

Dual cell surface expression of P-CAR1 (Table 9) and N-CARs listed in Table 10 assessed by multicolor flow cytometry in transduced NFAT-luciferase reporter Jurkat cells is shown in FIGS. 1 and 2. Dual cell surface expression of P-CAR1 (Table 9) and N-CARs listed in Table 10 assessed by multicolor flow cytometry in transduced NFkB-luciferase reporter Jurkat cells is shown in FIGS. 3 and 4. Dual cell surface expression of P-CAR2 (Table 9) and N-CARs listed in Table 10 assessed by multicolor flow cytometry in transduced NFAT-luciferase reporter Jurkat cells is shown in FIGS. 6 and 7. Dual cell surface expression of P-CAR2 and N-CARs listed in Table 10 assessed by multicolor flow cytometry in transduced NFkB-luciferase reporter Jurkat cells is shown in FIGS. 8 and 9.

Cells were sequentially transduced with P-CAR and N-CAR lentivirus, and selected for antibiotic-resistant clones after each transduction. Intracellular domains of the various N-CARs are shown above each dot plot. P-CAR expression was detected using a recombinant human CD19-mouse IgG Fc fusion protein followed by APC-conjugated F(ab′)2 goat anti-mouse Fcy (shown on x axis), and N-CAR expression was detected with a biotinylated recombinant human PSMA-human IgG1 Fc fusion protein followed by PE-conjugated streptavidin (y axis).

In Vitro T Cell Activation Assay

For coculture assays, effector Jurkat cells expressing different combinations of P- and N-CARs were cocultured with AAPCs expressing either CD19 (on-target), both CD19 and PSMA (off-target), or neither antigen (empty vector transduced). AAPC target cells were plated at a density of 20,000 cells per well in tissue culture-treated flat-bottom white 96-well plates (Corning COSTAR). Plates were incubated at 37° C. in 5% CO₂ for 24 hours, after which time media was removed and 100,000 Control ΔPD1- or test N-CAR-transduced luciferase reporter Jurkat cells expressing P-CAR1 or P-CAR2 were added to each well in a volume of 100 uL. After a 16-hour incubation at 37° C., 100 uL Bright-Glo luciferase substrate (Promega) was added per well, plates were shaken for 2 minutes, and relative luciferase units (RLU) quantified on a Perkin Elmer EnVision Multilabel Reader. Each Jurkat cell line was tested in sextuplicate and results presented as a ratio of the mean RLU value from coculture with off-target AAPCs to the mean RLU from coculture with target AAPCs.

FIGS. 5A, 5B and 5C show the inhibitory effect of various N-CARs on P-CAR1 induced T cell activation. Control ΔPD1- or test N-CAR-transduced luciferase reporter Jurkat cells expressing P-CAR1 were incubated with either CD19-expressing AAPCs or dual CD19+PSMA-expressing AAPCs, and luciferase activity was assessed 16h later. Data are expressed as a ratio of the mean RLU from co-culture with CD19+PSMA AAPCs/CD19 AAPCs. n=6 replicates per sample; data shown are the means±SEM. FIGS. 5A/5C and 5B show results using NFAT-luciferase reporter and NFkB-luciferase reporter Jurkat cells, respectively.

FIGS. 10A and 10B show the inhibitory effect of various N-CARs on P-CAR2 induced T cell activation. Control ΔPD1- or test N-CAR-transduced luciferase reporter Jurkat cells expressing P-CAR2 were incubated with either CD19-expressing or dual PSMA/CD19-expressing AAPCs, and luciferase activity was assessed 16h later. Data are expressed as a ratio of the mean RLU from co-culture with CD19+PSMA AAPCs/CD19 AAPCs. n=6 replicates per sample; data shown are the means±SEM. Figures. 10A and 10B show results using NFAT-luciferase reporter and NFkB-luciferase reporter Jurkat cells, respectively.

Example 4 Activity of P-CAR⁺/N-CAR⁺ T-Cells in Primary Human T-Cells

The N-CAR designed according to example 2 are also optionally tested in primary human T-cells to ensure that the results from example 3 obtained with Jurkat T-cells translate to primary cells. This can be done by first transducing N-CAR constructs into primary human T-cells obtained according to methods known to the skilled person and monitoring the attenuation of T-cell activation by anti-CD3/CD28 stimulation in the absence and presence of N-CAR antigen. In addition, the P-CAR and N-CAR constructs disclosed in example 3 can also be transduced into primary human T-cells and tested on CD19, PSMA, and CD19/PSMA cells.

Example 5 Activity of T-Cells Comprising P-CAR and N-CAR in Xenograft Studies

P-CAR and N-CAR constructs as disclosed in Example 3 can be transduced into primary human T-cells and tested for efficacy in xenograft studies in NSG animals transplanted with tumors expressing, either only CD19 or both CD19 and PSMA. NSG mice are transplanted with luciferase labeled 10⁵-10⁶ cells expressing either CD19 or CD19 and PSMA. A few days after engraftment, these animals are infused with 10⁴-10⁶ P-CAR⁺/N-CAR⁺ T-cells intravenously. The animals are dosed with luciferin prior to imaging on the IVIS imaging system routinely to monitor tumor load.

The invention is further illustrated by the following embodiments:

1. An inhibitory chimeric antigen receptor (N-CAR) comprising

an extracellular domain comprising an antigen binding domain,

a transmembrane domain,

an intracellular domain, and,

wherein the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TX₁₁YX₂X₃X₄, wherein

X₁ is an amino acid

X₂ is an amino acid

X₃ is an amino acid and

X₄ is V or I.

2. The N-CAR according to embodiment 1, wherein when the extracellular domain is a scFv against PSMA, then the intracellular domain is not the intracellular domain of human PD-1.

3. The N-CAR according to embodiment 1 or 2, wherein the extracellular domain does not bind to PMSA.

4. The N-CAR according to any one of embodiments 1 to 3, wherein the intracellular domain does not comprise the full intracellular domain of PD-1.

5. The N-CAR according to any one of embodiments 1 to 4, wherein ITSM motif is not TEYATI.

5.1 The N-CAR according to any one of embodiments 1 to 5, wherein the intracellular domain is not the intracellular domain of human PD1.

5.2 The N-CAR according to any one of embodiments 1 to 5, wherein the intracellular domain is not the intracellular domain of human BTLA.

5.3 The N-CAR according to any one of embodiments 1 to 5, wherein the intracellular domain is not the intracellular domain of human CD244.

5.4 The N-CAR according to any one of embodiments 1 to 5, wherein the intracellular domain is not SEQ ID No 2000, SEQ ID No 2001 or SEQ ID No 2002.

6. The N-CAR according to any one of embodiments 1 to 5.4, wherein the intracellular domain comprises the sequence ((1_(1—)1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) , wherein

n is 0, 1 or an integer greater than 1;

m is 1 or an integer greater than 1;

p is 1 or an integer greater than 1;

L1 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (a) a naturally occurring N-terminal flanking region of an ITIM         only intracellular domains or a fragment thereof;     -   (b) a naturally occurring N-terminal flanking region of an         ITIM.*ITSM intracellular domains or a fragment thereof;     -   (c) a naturally occurring intracellular domain from a known         inhibitory receptor, wherein the said intracellular domain is         N-terminally flanking to a sequence in (c) above, or a fragment         thereof; and,     -   (d) a non-naturally occurring sequence comprising between 1 and         500 amino acids;

each of L2 and L3 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (e) a naturally occurring C-terminal flanking region of an ITIM         only intracellular domain or a fragment thereof;     -   (f) a naturally occurring N-terminal flanking region of an ITSM         only intracellular domain or a fragment thereof;     -   (g) a naturally occurring intracellular domain between ITIM and         ITSM from proteins that have ITIM.*ITSM motif or a fragment         thereof;     -   (h) a naturally occurring intracellular domain from a known         inhibitory receptor wherein the said intracellular domain is         N-terminally flanking to a sequence in (0 or (g) above, or a         fragment thereof; and     -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

L4 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (j) a naturally occurring C-terminal flanking region of an         ITIM.*ITSM intracellular domain or a fragment thereof;     -   (k) a naturally occurring C-terminal flanking region of an ITSM         only intracellular domain or a fragment thereof;     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor wherein the said intracellular domain is         C-terminally flanking to a sequence in (j) or (k) above; or a         fragment thereof and     -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids,

the ITIM is the sequence X₅X₆YX₇X₈X₉, wherein

X₅ is S, V, I or L,

X₆ is an amino acid,

X₇ is an amino acid,

X₈ is an amino acid, and,

X₉ is V, I or L, and

the ITSM is the sequence TX₁₁YX₂X₃X₄, wherein

X₁ is an amino acid,

X₂ is an amino acid,

X₃ is an amino acid, and,

X₄ is V or I,

or a variant thereof.

7. The N-CAR according to embodiment 6, wherein

L1 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (a) a naturally occurring N-terminal flanking region of ITIM         only intracellular domains selected from the sequences shown in         Table 3 or a fragment thereof;     -   (b) a naturally occurring N-terminal flanking region of         ITIM.*ITSM intracellular selected from the sequences shown in         Table 1 or a fragment thereof;     -   (c) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in Table 2         or a fragment thereof, wherein said intracellular domain is         N-terminally flanking to a sequence in (b) above, or a fragment         thereof; and     -   (d) a non-naturally occurring sequence comprising between 1 and         500 amino acids;

each of L2 and L3 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (e) a naturally occurring C-terminal flanking region of ITIM         only intracellular domains selected from the sequences shown in         Table 4 or a fragment thereof;     -   (f) a naturally occurring N-terminal flanking region of ITSM         only intracellular domains selected from the sequences shown in         Table 6, or a fragment thereof;     -   (g) a naturally occurring intracellular domain between ITIM and         ITSM from proteins that have ITIM.*ITSM motif selected from the         sequences shown in Table 5, or a fragment thereof;     -   (h) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in Table 2         or a fragment thereof wherein said intracellular domain is         N-terminally flanking to a sequence in (f) or (g) above, or a         fragment thereof; and     -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

L4 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (j) a naturally occurring C-terminal flanking region of         ITIM.*ITSM intracellular domains selected from the sequences         shown in Table 7, or a fragment thereof;     -   (k) a naturally occurring C-terminal flanking region of ITSM         only intracellular domains selected from the sequences shown in         Table 8, or a fragment thereof;     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in Table 2         or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (I) above, or a fragment         thereof; and,     -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids.

8. The N-CAR according to embodiment 6 or 7 wherein the intracellular domain comprises the sequence (L1-ITIM-L2-L3-ITSM-L4)^(p) wherein

p is 1, 2, 3, 4 or 5;

L1 is a naturally occurring N-terminal flanking region of an ITIM only intracellular domain or a fragment thereof such as, for example, any of the sequences shown in Table 3 or a fragment thereof;

L2 is absent;

L3 is a naturally occurring a naturally occurring intracellular domain between ITIM and ITSM from proteins that have ITIM.*ITSM motif or a fragment thereof such as, for example, any of the sequences shown in Table 5 or a fragment thereof;

L4 is a naturally occurring C-terminal flanking region of an ITIM.*ITSM intracellular domain or a fragment thereof such as, for example, any of the sequences shown in Table 7 or a fragment thereof; or a naturally occurring C-terminal flanking region of an ITSM only intracellular domain such as, for example, any of the sequences shown in Table 8 or a fragment thereof.

9. The N-CAR according to any one of embodiments 6 to 8 wherein L1 is absent or comprises one or more, preferably one, sequences or selected from the group consisting of:

-   -   (a) a naturally occurring N-terminal flanking region of ITIM         only intracellular domains selected from

YKMYGSEMLHKRDPLDEDEDTD DHWALTQRTARAVSPQSTKPMAES CSRAARGTIGARRTGQPLKEDPSAVPVFS HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDRET DTSALAAGSSQE KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEE LTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCG EQRGEDCAELHDYFNV KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSD RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPG WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKED KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTY

-   -   (b) a naturally occurring N-terminal flanking region of         ITIM.*ITSM intracellular domains selected from

YKMYGSEMLHKRDPLDEDEDTD WRMMKYQQKAAGMSPEQVLQPLEGD CSRAARGTIGARRTGQPLKEDPSAVPVFS RIRQKKAQGSTSSTRLHEPEKNAREITQDTND KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEE KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSD RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPG KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTY

-   -   (c) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table         2, wherein said intracellular domain is N-terminally flanking to         a sequence in (b) above; and     -   (d) a non-naturally occurring sequence comprising between 1 and         500 amino acids.

10. A N-CAR according to any one of embodiments 6 to 9 wherein each of L2 and L3 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (e) a naturally occurring C-terminal flanking region of ITIM         only intracellular domains selected from;

GNCSFFTETG NFHGMNPSKDTSTEYSEVRTQ KEEEMADTSYGTVKAENIIMMETAQTSL NHSVIGPNSRLARNVKEAPTEYASICVRS DHWALTQRTARAVSPQSTKPMAESITYAAVARH QVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT DFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQP LRPEDGHCSWPL NLPKGKKPAPQAAEPNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRTP KQPAPKPEPSFSEYASVQVPRK TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED QEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTVC VADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAFGV TMWEIATRGMTPYPGVQNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWR TDPLDRPTFSVLRLQLEKLLESLPDVRNQADVIYVNTQLLESSEGLAQGS TLAPLDLNIDPDSIIASCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEW EDLTSAPSAAVTAEKNSVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFA DDSSEGSEVLM

-   -   (f) a naturally occurring N-terminal flanking region of ITSM         only intracellular domains selected from;

YKMYGSEMLHKRDPLDEDEDTDISYKKLKEEEMAD CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA AEPNNH KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEELHYASLNFHGMNPSKDTS KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEA P WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI QSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPP ASARSSVGEGELQYASLSFQMVKPWDSRGQEATD NKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQGH IIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKM LVAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVF EYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMV YLAGLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYS KLARHSKFGMKGPASVISNDDDSASPLHHISNGSNTPSSSEGGPDAVIIG MTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFL AECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFY GVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQML HIAQQIAAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYS KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSA KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTYLLYSRLETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAA RNCMLRDDMTVCVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRV YTSKSDVWAFGVTMWEIATRGM

-   -   (g) a naturally occurring intracellular domain between ITIM and         ITSM from proteins that have ITIM.*ITSM motif selected from;

KEEEMAD NFHGMNPSKDTS QVSSAESHKDLGKKDTE NLPKGKKPAPQAAEPNNH NHSVIGPNSRLARNVKEAP DFQWREKTPEPPVPCVPEQ TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED QEPTYCNMGHLSSHLPGRGPEEP ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTVC VADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAFGV TMWEIATRGM

-   -   (h) a naturally occurring intracellular domain from known         inhibitory receptors selected from the sequences shown in table         2 wherein said intracellular domain is N-terminally flanking to         a sequence in (f) or (g) above; and     -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

11. The N-CAR according to according to any one of embodiments 6 to 10 wherein L4 is absent or comprises one or more, preferably one, sequences selected from the group consisting of:

-   -   (j) a naturally occurring C-terminal flanking region of         ITIM.*ITSM intracellular domains selected from:

SRP RTQ CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM

-   -   (k) a naturally occurring C-terminal flanking region of ITSM         only intracellular domain selected from:

RTQ SRP KIHR CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT RKPQVVPPPQQNDLEIPESPTYENFT GKSQPKAQNPARLSRKELENFDVYS VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK FNLQGKTPVSQKEESSATIYCSIRKPQVVPPPQQNDLEIPESPTYENFT GGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSN TEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQA LAQAPPVYLDVLG GGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSN NEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTLLQN LAKASPVYLDILG QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM KDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSR KSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS

-   -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table 2         wherein said intracellular domain is C-terminally flanking to a         sequence in (j) or (k) above; and     -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids.

11.1. The N-CAR according to embodiment 6 wherein the intracellular domain comprises the following sequence:

((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) , wherein

n is 0;

m is 1;

p is 1;

L3 comprises one sequence selected from

-   -   (f) a naturally occurring N-terminal flanking region of an ITSM         only intracellular domain such as, for example, any of the         sequences shown in Table 6 below or a fragment thereof; or,     -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

L4 comprises one or more, preferably one or two, sequences selected from the group consisting of:

-   -   (k) a naturally occurring C-terminal flanking region of an ITSM         only intracellular domain such as, for example, any of the         sequences shown in Table 8 below or a fragment thereof;     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor such as any of the sequences shown in table         2 or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above; and     -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids, and, wherein.

11.2. The N-CAR according to embodiment 6 wherein the intracellular domain comprises the following sequence:

((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) , wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

YKMYGSEMLHKRDPLDEDEDTDISYKKLKEEEMAD CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA AEPNNH KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEELHYASLNFHGMNPSKDTS KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEA P WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI QSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPP ASARSSVGEGELQYASLSFQMVKPWDSRGQEATD NKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQGH IIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKM LVAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVF EYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMV YLAGLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYS KLARHSKFGMKGPASVISNDDDSASPLHHISNGSNTPSSSEGGPDAVIIG MTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFL AECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFY GVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQML HIAQQIAAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYS KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSA KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTYLLYSRLETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAA RNCMLRDDMTVCVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRV YTSKSDVWAFGVTMWEIATRGM

and L4 comprises one sequence selected from the group consisting of

(k)

RTQ SRP KIHR CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT RKPQVVPPPQQNDLEIPESPTYENFT GKSQPKAQNPARLSRKELENFDVYS VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK FNLQGKTPVSQKEESSATIYCSIRKPQVVPPPQQNDLEIPESPTYENFT GGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSN TEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQA LAQAPPVYLDVLG GGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSN NEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTLLQN LAKASPVYLDILG QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM KDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSR KSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS

and optionally

-   -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor such as any of the sequences shown in table         2 or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above. 11.3. The         N-CAR according to embodiment 6 wherein the intracellular domain         comprises the following sequence:

((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) , wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA AEPNNH KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEA P WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI QSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPP ASARSSVGEGELQYASLSFQMVKPWDSRGQEATD KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSA

L4 comprises one sequence selected from the group consisting of

(k)

SRP KIHR CVRS RKAVPDAVESRYSRTEGSLDGT RKPQVVPPPQQNDLEIPESPTYENFT GKSQPKAQNPARLSRKELENFDVYS VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK and optionally

-   -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table         2, preferably KIR2DL2, or a fragment thereof wherein said         intracellular domain is C-terminally flanking to a sequence         in (k) above. 11.4. The N-CAR according to embodiment 6 wherein         the intracellular domain comprises the following sequence:

((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ

and L4 comprises

(k)

VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL

-   -   and     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table         2, preferably KIR2DL2, or a fragment thereof wherein said         intracellular domain is C-terminally flanking to a sequence         in (k) above. 11.5. The N-CAR according to embodiment 6 wherein         the intracellular domain comprises the following sequence:

((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein

n is 0;

m is 1;

p is 1;

L3 is selected from

WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP

L4 comprises a sequence selected from

(k)

SRP

-   -   and optionally     -   (l) a naturally occurring intracellular domain from a known         inhibitory receptor selected from the sequences shown in table 2         or a fragment thereof wherein said intracellular domain is         C-terminally flanking to a sequence in (k) above.

11.6. The N-CAR according to embodiment 6 wherein the intracellular domain comprises the following sequence:

((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p) , wherein

n is 0;

m is 1;

p is 1 or 2;

L3 comprises one sequence selected from

-   -   (i) a non-naturally occurring sequence comprising between 1 and         500 amino acids; and

L4 comprises one or more, preferably one or two, sequences selected from:

-   -   (m) a non-naturally occurring sequence comprising between 1 and         500 amino acids.

11.7. The N-CAR according to embodiment 6 wherein the intracellular domain is selected from SEQ ID No 2000, SEQ ID No 2001, SEQ ID No 2002, SEQ ID No 2003, SEQ ID No 2004, SEQ ID No 2005, SEQ ID No 2006, SEQ ID No 2007, SEQ ID No 2008, SEQ ID No 2009, SEQ ID No 2010, SEQ ID No 2011, SEQ ID No 2012, SEQ ID No 2013, SEQ ID No 2014, SEQ ID No 2015, SEQ ID No 2016 and SEQ ID No 2017.

12. The N-CAR according to any one of embodiments 6 to 11.7 wherein the non-naturally occurring sequence of (d), (i) and (m) comprises between 1 and 400, 1 and 300, 1 and 200, 1 and 100, 10 and 100, 10 and 80, 10 and 60, 10 and 40, 100 and 200, 100 and 300 or 100 and 400.

13. The N-CAR according to any one of embodiments 6 to 11.7 wherein the non-naturally occurring sequence of (d) or (i) is a Glycine/Serine linker (Gly_(x)Ser)_(n) where x=1, 2, 3, 4 or 5 and n is 1 to 100.

14. The N-CAR according to embodiment 13 wherein the non-naturally occurring sequence of (d) or (i) is a Glycine/Serine linker (Gly-Gly-Gly-Ser)_(n) or (Gly-Gly-Gly-Gly-Ser)_(n), where n is 1 to 100, 1 to 80, 1 to 50, 1 to 20 or 1 to 10.

15. The N-CAR according to embodiment 14 wherein the non-naturally occurring sequence of (d) or (i) is a (Gly₄Ser)₄ or (Gly₄Ser)₃.

16. The ICAR according to any one of embodiments 6 to 15 wherein the intracellular domain comprises the sequence (L1-ITIM-L2-L3-ITSM-L4)^(p) wherein

p is 1, 2, 3, 4 or 5;

L1 is a naturally occurring N-terminal flanking region of ITIM only intracellular domains selected from the following sequences;

YKMYGSEMLHKRDPLDEDEDTD DHWALTQRTARAVSPQSTKPMAES CSRAARGTIGARRTGQPLKEDPSAVPVFS HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDRET DTSALAAGSSQE KTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTV EMDEE LTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCG EQRGEDCAELHDYFNV KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSD RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPG WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKED KRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNK LEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNS SQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKY GDLHTY

L2 is absent;

L3 is a naturally occurring intracellular domain between ITIM and ITSM from proteins that have ITIM.*ITSM motif selected from the following sequences:

KEEEMAD NFHGMNPSKDTS QVSSAESHKDLGKKDTE NLPKGKKPAPQAAEPNNH NHSVIGPNSRLARNVKEAP DFQWREKTPEPPVPCVPEQ TLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAED QEPTYCNMGHLSSHLPGRGPEEP ETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTVC AVDFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAFGV TMWEIATRGM

L4 is a naturally occurring C-terminal flanking region of ITIM.*ITSM intracellular domains selected from the following sequences:

SRP RTQ CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM

or a naturally occurring C-terminal flanking region of ITSM only intracellular domains selected from the following sequences:

RTQ SRP CVRS KAENIIMMETAQTSL RKAVPDAVESRYSRTEGSLDGT VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK FNLQGKTPVSQKEESSATIYCSIRKPQVVPPPQQNDLEIPESPTYENFT GGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSN TEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQA LAQAPPVYLDVLG GGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSN NEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTLLQN LAKASPVYLDILG QNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQL EKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIA SCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKN SVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM KDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSR KSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS.

17. The N-CAR according to any one of the preceding embodiments wherein the term amino acid refers to glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, cysteine, methionine, lysine, arginine, histidine, tryptophan, aspartic acid, glutamic acid, asparagine or glutamine.

18. The N-CAR according to any one of the preceding embodiments wherein X₁ is E, V or I.

19. The N-CAR any one of the preceding embodiments wherein X₁ is E.

20. The N-CAR any one of the preceding embodiments wherein X₂ is S or A.

21. The N-CAR any one of the preceding embodiments wherein X₂ is A.

22. The N-CAR any one of the preceding embodiments wherein X₃ is E, S, T, Q or V.

23. The N-CAR any one of the preceding embodiments wherein X₃ is E.

24. The N-CAR any one of the preceding embodiments wherein X₃ is T.

25. The N-CAR any one of the preceding embodiments wherein X₂ is I.

26. The N-CAR according to any one of embodiments 7 to 25 wherein X₅ is L, V or I

27. The N-CAR according to any one of embodiments 7 to 26 wherein X₅ is L.

28. The N-CAR according to any one of embodiments 7 to 26 wherein X₅ is V

29. The N-CAR according to any one of embodiments 7 to 26 wherein X₅ is I.

30. The N-CAR according to any one of embodiments 7 to 29 wherein X₆ is A, H, Q, T, D, V, L or E.

31. The N-CAR according to any one of embodiments 7 to 30 wherein X₆ is H.

32. The N-CAR according to any one of embodiments 7 to 30 wherein X₆ is D.

33. The N-CAR according to any one of embodiments 7 to 32 wherein X₇ is A, G, T, V or E.

34. The N-CAR according to any one of embodiments 7 to 33 wherein X₇ is A.

35. The N-CAR according to any one of embodiments 7 to 33 wherein X₇ is G.

36. The N-CAR according to any one of embodiments 7 to 35 wherein X₈ is V, S, D or E.

37. The N-CAR according to any one of embodiments 7 to 36 wherein X₈ is S or E.

38. The N-CAR according to any one of embodiments 7 to 37 wherein X₈ is E.

39. The N-CAR according to any one of embodiments 7 to 38 wherein X₉ is L or V.

40. The N-CAR according to any one of embodiments 7 to 38 wherein X₉ is L.

41. The N-CAR according to any one of embodiments 7 to 40 wherein X₅ is L or V, X₈ is E and X₉ is L.

42. The N-CAR any one of the preceding embodiments wherein the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain, is selected from TAYELV, TAYGLI, TAYNAV, TCYGLV, TCYPDI, TDYASI, TDYDLV, TDYLSI, TDYQQV, TDYYRV, TEYASI, TEYATI, TEYDTI, TEYPLV, TEYSEI, TEYSEV, TEYSTI, TEYTKV, TFYHVV, TFYLLI, TFYNKI, TFYPDI, TGYEDV, TGYLSI, THYKEI, TIYAQV, TIYAVV, TIYCSI, TIYEDV, TIYERI, TIYEVI, TIYHVI, TIYIGV, TIYLKV, TIYSMI, TIYSTI, TIYTYI, TKYFHI, TKYMEI, TKYQSV, TKYSNI, TKYSTV, TLYASV, TLYAVV, TLYFWV, TLYHLV, TLYPMV, TLYPPI, TLYRDI, TLYRDV, TLYSKI, TLYSLI, TLYSPV, TMYAQV, TMYCQV, TNYKAV, TNYNLV, TPYAGI, TPYPGV, TPYVDI, TQYGRV, TQYNQV, TRYAYV, TRYGEV, TRYHSV, TRYKTI, TRYLAI, TRYMAI, TRYQKI, TRYQQI, TRYSNI, TRYSPI, TSYGTV, TSYMEV, TSYQGV, TSYTTI, TTYRSI, TTYSDV, TTYVTI, TVYAQI, TVYASV, TVYEVI, TVYGDV, TVYKGI, TVYQRV, TVYSEV, TVYSTV, TYYHSI, TYYLQI, or TYYYSV.

43. The N-CAR any one of the preceding embodiments wherein the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TEYASI.

44. The N-CAR any one of the preceding embodiments wherein the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TEYSEI.

44.1 The N-CAR any one of the preceding embodiments wherein the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TEYSTI.

45. The N-CAR any one of the preceding embodiments wherein the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is TVYSEV.

46. The N-CAR according to any one of embodiments 7 to 45 wherein the ITIM, or at least one of the ITIMs when several ITSMs are present in the intracellular domain is selected from LSYRSL, LPYYDL, LPYYDL, LLYSRL, LLYSRL, LIYTLL, LLYADL, ISYTTL, VTYSAL, IHYSEL, VDYVIL, LHYASL, LDYDYL, VDYDFL, VTYSTL, IIYSEV, LEYLCL, VLYGQL, VPYTPL, ISYPML, ISYPML, ISYPML, VSYTNL, LLYEMV, VDYNLV, ITYFAL, VHYQSV, VPYVMV, IPYRTV, IAYSLL, VCYGRL, LKYLYL, LLYEHV, ITYSLL, VLYSEL, IWYNIL, ISYKGL, IDYYNL, LEYLQL, LKYRGL, VLYASV, LQYLSL, LFYRHL, VQYKAV, LSYSSL, LSYTKV, VQYSTV, VKYNPV, VVYSEV, VVYSEV, IIYSEV, LEYVSV, LAYHTV, VQYLRL, VTYTQL, IVYTEL, VTYTQL, IVYAEL, VTYAQL, IVYTEL, VTYAQL, IVYTEL, VTYAQL, VTYAQL, VTYAQL, ILYTEL, VTYAQL, VTYAQL, ITYAAV, VTYAQL, ITYAAV, VIYIDV, VTYAEV, VTYAQL, VTYAQL, VTYAPV, VTYAQL, VTYAKV, VTYARL, VTYAQL, ILYHTV, LLYSRL, VLYAML, VIYAQL, LVYENL, LCYADL, ISYASL, LTYVLL, VTYVNL, VRYSIV, VFYRQV, VFYRQV, LKYMEV, LKYMEV, VDYGEL, LSYMDL, VLYTAV, VQYTEV, IVYASL, VEYLEV, LEYVDL, ITYADL, LTYADL, ITYADL, LTYADL, VIYENV, VIYENV, VIYENV, VIYENV, LAYYTV, VSYSAV, LVYDKL, LNYMVL, LNYACL, LDYINV, LHYATL, LHYASL, LHYASL, LHYAVL, IQYAPL, IQYASL, IQYASL, LLYLLL, VVYSQV, VIYSSV, VVYSQV, VIYSSV, VVYYRV, VPYVEL, LDYDKL, LPYYDL, LSYPVL, VAYSQV, LFYWDV, LFYWDV, LIYSQV, or LDYEFL.

47. The N-CAR according to any one of embodiments 7 to 45 wherein the ITIM, or at least one of the ITIMs when several ITSMs are present in the intracellular domain is selected IAYGDI, IAYRDL, IAYSLL, IAYSRL, ICYALL, ICYDAL, ICYPLL, ICYQLI, IDYILV, IDYKTL, IDYTQL, IDYYNL, IEYCKL, IEYDQI, IEYGPL, IEYIRV, IEYKSL, IEYKTL, IEYSVL, IEYWGI, IFYGNV, IFYHNL, IFYKDI, IFYQNV, IFYRLI, IGYDIL, IGYDVL, IGYICL, IGYKAI, IGYLEL, IGYLPL, IGYLRL, IGYPFL, IGYSDL, IHYRQI, IHYSEL, IIYAFL, IIYHVI, IIYMFL, IIYNLL, IIYNNL, IIYSEV, IKYCLV, IKYKEL, IKYLAL, IKYTCI, ILYADI, ILYAFL, ILYCSV, ILYEGL, ILYELL, ILYFQI, ILYHTV, ILYLQV, ILYSIL, ILYSVL, ILYTEL, ILYTIL, IMYTLV, INYCSV, INYKDI, INYTTV, INYVLL, IPYDVL, IPYLLV, IPYRTV, IPYSQL, IPYSRI, IPYTQI, IQYAPL, IQYASL, IQYERL, IQYGII, IQYGNV, IQYGRV, IQYNVV, IQYRSI, IQYTEL, IQYWGI, IRYANL, IRYLDL, IRYPLL, IRYRLL, IRYRTI, ISYASL, ISYCGV, ISYEPI, ISYFQI, ISYGLI, ISYKKL, ISYLPL, ISYPML, ISYTTL, ITYAAV, ITYADL, ITYAEL, ITYAEV, ITYASV, ITYDLI, ITYENV, ITYQLL, ITYSLL, IVYAEL, IVYALV, IVYASL, IVYEIL, IVYFIL, IVYHML, IVYLCI, IVYRLL, IVYSAL, IVYSWV, IVYTEL, IVYYIL, IWYENL, IWYFVV, IWYNIL, IYYLGV, LAYALL, LAYARI, LAYDSV, LAYFGV, LAYHRL, LAYKDL, LAYKRI, LAYPPL, LAYQTL, LAYREV, LAYRII, LAYRLL, LAYSQL, LAYSSV, LAYTLL, LAYWGI, LAYYTV, LCYADL, LCYAIL, LCYFHL, LCYHPI, LCYKEI, LCYKFL, LCYMII, LCYRKI, LCYRVL, LCYSTV, LCYTLV, LDYASI, LDYCEL, LDYDKI, LDYDKL, LDYDYL, LDYDYV, LDYEFL, LDYINV, LDYNNL, LDYPHV, LDYSPV, LDYVEI, LDYWGI, LEYAPV, LEYIPL, LEYKTI, LEYLCL, LEYLKL, LEYLQI, LEYLQL, LEYQRL, LEYVDL, LEYVSV, LEYYQI, LFYAQL, LFYCSV, LFYERV, LFYGFL, LFYKYV, LFYLLL, LFYNKV, LFYRHL, LFYTLL, LFYWDV, LFYWKL, LGYGNV, LGYKEL, LGYLQL, LGYPLI, LGYPWV, LGYSAL, LGYSDL, LGYVTL, LHYAKI, LHYALV, LHYANL, LHYARL, LHYASI, LHYASL, LHYASV, LHYATI, LHYATL, LHYAVL, LHYDVV, LHYEGL, LHYETI, LHYFEI, LHYFVV, LHYGAI, LHYILI, LHYINL, LHYKRI, LHYLDL, LHYLNI, LHYLTI, LHYLVI, LHYMAI, LHYMII, LHYMNI, LHYMTI, LHYMTL, LHYMTV, LHYMVI, LHYNML, LHYPAL, LHYPDL, LHYPII, LHYPIL, LHYPLL, LHYPML, LHYPNV, LHYPSI, LHYPTI, LHYPTL, LHYPTV, LHYPVI, LHYPVL, LHYRII, LHYRTI, LHYSII, LHYSSI, LHYSTI, LHYSTL, LHYSVI, LHYTAI, LHYTAL, LHYTII, LHYTKV, LHYTLI, LHYTSI, LHYTTI, LHYTTV, LHYTVI, LHYTVL, LHYTVV, LHYVSI, LHYVTI, LHYVVI, LIYEKL, LIYENV, LIYKDL, LIYNSL, LIYSGL, LIYTLL, LIYTVL, LIYWEI, LKYCEL, LKYDKL, LKYESL, LKYFTI, LKYHTV, LKYILL, LKYIPI, LKYKHV, LKYLYL, LKYMEV, LKYMTL, LKYPAI, LKYPDV, LKYPEL, LKYQPI, LKYRGL, LKYRLL, LLYADL, LLYAPL, LLYAVV, LLYCAI, LLYEHV, LLYELL, LLYEQL, LLYGQI, LLYIRL, LLYKAL, LLYKFL, LLYKLL, LLYKTV, LLYMVV, LLYNAI, LLYNIV, LLYNVI, LLYPAI, LLYPLI, LLYPNI, LLYPSL, LLYPTI, LLYPVI, LLYPVV, LLYQIL, LLYQNI, LLYRLL, LLYRVI, LLYSII, LLYSLI, LLYSPV, LLYSRL, LLYSTI, LLYSVI, LLYSVV, LLYTTI, LLYTVI, LLYTVV, LLYVII, LLYVIL, LLYVTI, LLYWGI, LLYYLL, LLYYVI, LMYDNV, LMYMVV, LMYQEL, LMYRGI, LNYACL, LNYATI, LNYEVI, LNYGDL, LNYHKL, LNYMVL, LNYNIV, LNYPVI, LNYQMI, LNYSGV, LNYSVI, LNYTIL, LNYTTI, LNYVPI, LPYADL, LPYALL, LPYFNI, LPYFNV, LPYHDL, LPYKLI, LPYKTL, LPYLGV, LPYLKV, LPYPAL, LPYQVV, LPYRTV, LPYVEI, LPYYDL, LQYASL, LQYERI, LQYFAV, LQYFSI, LQYHNI, LQYIGL, LQYIKI, LQYLSL, LQYMIV, LQYPAI, LQYPLL, LQYPLV, LQYPSI, LQYPTL, LQYPVL, LQYRAV, LQYSAI, LQYSSI, LQYSVI, LQYTIL, LQYTLI, LQYTMI, LQYYQV, LRYAAV, LRYAGL, LRYAPL, LRYASI, LRYATI, LRYATV, LRYAVL, LRYCGI, LRYELL, LRYETL, LRYGAL, LRYGPI, LRYGTL, LRYHHI, LRYHSI, LRYHVL, LRYIAI, LRYIFV, LRYITV, LRYKEV, LRYKKL, LRYKMV, LRYKSL, LRYKVI, LRYLAI, LRYLDL, LRYLTI, LRYLTV, LRYMSI, LRYMVI, LRYNCI, LRYNGL, LRYNII, LRYNIL, LRYNKI, LRYNSL, LRYNVI, LRYNVL, LRYPFL, LRYPII, LRYPIL, LRYPLL, LRYPNI, LRYPSI, LRYPTI, LRYPTL, LRYPVI, LRYPVL, LRYQKL, LRYQMI, LRYQNL, LRYRLI, LRYRVI, LRYSAI, LRYSDL, LRYSII, LRYSMI, LRYSSI, LRYSTI, LRYSTL, LRYSVI, LRYSVL, LRYSVV, LRYTAI, LRYTIL, LRYTLI, LRYTMI, LRYTNL, LRYTPV, LRYTSI, LRYTSV, LRYTTI, LRYTTV, LRYTVI, LRYVEV, LRYVTI, LRYVTV, LSYDSL, LSYEDV, LSYFGV, LSYILI, LSYISV, LSYKQV, LSYKRL, LSYLDV, LSYMDL, LSYNAL, LSYNDL, LSYNKL, LSYNQL, LSYPVL, LSYQEV, LSYQPV, LSYQTI, LSYRSL, LSYRSV, LSYSII, LSYSSL, LSYSTL, LSYTKV, LSYTSI, LSYTTI, LSYVLI, LTYADL, LTYAEL, LTYAQV, LTYARL, LTYCDL, LTYCGL, LTYCVL, LTYEEL, LTYEFL, LTYGEV, LTYGRL, LTYKAL, LTYLRL, LTYMTL, LTYNTL, LTYPGI, LTYQSV, LTYSSV, LTYTTV, LVYDAI, LVYDKL, LVYDLV, LVYENL, LVYGQL, LVYHKL, LVYQEV, LVYRKV, LVYRNL, LVYSEI, LVYTNV, LVYWEI, LVYWKL, LVYWRL, LWYEGL, LWYKYI, LWYNHI, LWYTMI, LYYCQL, LYYGDL, LYYKKV, LYYLLI, LYYPKV, LYYRRV, LYYSTI, LYYVRI, LYYVVI, SAYATL, SAYCPL, SAYPAL, SAYQAL, SAYQTI, SAYRSV, SAYTAL, SAYTPL, SAYVVL, SCYAAV, SCYCII, SCYCLL, SCYDFL, SCYEEL, SCYEKI, SCYHIL, SCYPYI, SCYRIL, SCYRTL, SDYCNL, SDYEDL, SDYENV, SDYESV, SDYFIV, SDYHTL, SDYLAI, SDYLDI, SDYLEL, SDYQDL, SDYQRL, SDYSVI, SDYTHL, SEYASV, SEYEEL, SEYFEL, SEYGEL, SEYITL, SEYKAL, SEYKEL, SEYKGI, SEYLAI, SEYLEI, SEYMVI, SEYQSI, SEYRPI, SEYSEI, SEYSSI, SEYTPI, SEYTYV, SFYAAL, SFYDSL, SFYKGL, SFYLYV, SFYNAV, SFYPSV, SFYQQI, SFYQQL, SFYSAL, SFYSDI, SFYSKL, SFYSRV, SFYWNV, SFYYLI, SGYAQL, SGYATL, SGYEKL, SGYQLV, SGYQRI, SGYRRL, SGYSHL, SGYSQL, SGYTLI, SGYTRI, SGYYRV, SHYADV, SHYFPL, SHYIDI, SHYKRL, SHYQVV, SIYAPL, SIYATL, SIYEEL, SIYEEV, SIYELL, SIYEVL, SIYGDL, SIYKKL, SIYLNI, SIYLVI, SIYRYI, SIYSWI, SKYKEI, SKYKIL, SKYKSL, SKYLAV, SKYLGV, SKYNIL, SKYQAV, SKYSDI, SKYSSL, SKYVGL, SKYVSL, SLYANI, SLYAQV, SLYAYI, SLYDDL, SLYDFL, SLYDNL, SLYDSI, SLYDYL, SLYEGL, SLYEHI, SLYELL, SLYHCL, SLYHKL, SLYIGI, SLYKKL, SLYKNL, SLYLAI, SLYLGI, SLYNAL, SLYNLL, SLYRNI, SLYSDV, SLYTCV, SLYTTL, SLYVAI, SLYVDV, SLYVSI, SLYYAL, SLYYNI, SLYYPI, SMYDGL, SMYEDI, SMYNEI, SMYQSV, SMYTWL, SMYVSI, SNYENL, SNYGSL, SNYGTI, SNYLVL, SNYQEI, SNYRLL, SNYRTL, SNYSDI, SNYSLL, SPYAEI, SPYATL, SPYEKV, SPYGDI, SPYGGL, SPYNTL, SPYPGI, SPYPGV, SPYQEL, SPYRSV, SPYSRL, SPYTDV, SPYTSV, SPYVVI, SQYCVL, SQYEAL, SQYKRL, SQYLAL, SQYLRL, SQYMHV, SQYSAV, SQYTSI, SQYWRL, SRYAEL, SRYATL, SRYESL, SRYGLL, SRYLSL, SRYMEL, SRYMRI, SRYPPV, SRYQAL, SRYQQL, SRYRFI, SRYRFV, SRYSAL, SRYSDL, SRYTGL, SRYVRL, SSYDEL, SSYEAL, SSYEIV, SSYEPL, SSYGRL, SSYGSI, SSYGSL, SSYHII, SSYHIL, SSYHKL, SSYHNI, SSYIKV, SSYNSV, SSYQEI, SSYRKV, SSYRRV, SSYSDI, SSYTPL, SSYTRL, SSYTSV, SSYTTI, SSYVKL, STYAEV, STYAGI, STYAHL, STYALV, STYAPI, STYDHV, STYDKV, STYDQV, STYDRI, STYEEL, STYEYL, STYILV, STYLPL, STYMAV, STYQTL, STYRKL, STYSQL, STYTSI, STYYQV, SVYATL, SVYCFL, SVYCNL, SVYDSV, SVYDTI, SVYEKV, SVYEML, SVYGSV, SVYPII, SVYQPI, SVYRKV, SVYSHL, SVYSRV, SVYTAL, SVYTEL, SVYWKV, SWYDSI, SWYFTV, SYYKAI, SYYLKL, SYYSFV, SYYVTI, VAYADL, VAYARI, VAYARV, VAYDQL, VAYGHV, VAYKQV, VAYKRL, VAYNLL, VAYQRV, VAYSGV, VAYSQV, VCYCIV, VCYGLV, VCYGRL, VCYIVV, VCYLLV, VDYDCI, VDYDFL, VDYFTI, VDYFVL, VDYGEL, VDYILV, VDYIQV, VDYKNI, VDYMSI, VDYNLV, VDYPDV, VDYSDL, VDYSSV, VDYTTL, VDYVDV, VDYVGV, VDYVIL, VDYVQV, VEYAPL, VEYDPL, VEYGTI, VEYHRL, VEYLEV, VEYQLL, VEYRPL, VEYSSI, VEYSTV, VFYAEI, VFYLAV, VFYRQV, VFYVGV, VFYYVI, VFYYVL, VGYETI, VHYALL, VHYARL, VHYETL, VHYGGV, VHYHSL, VHYIPV, VHYKEI, VHYLQV, VHYNSL, VHYQSV, VHYRSL, VIYAQL, VIYDRL, VIYENV, VIYEPL, VIYERL, VIYIDV, VIYKKI, VIYKRI, VIYPFL, VIYPNI, VIYSDL, VIYSML, VIYSSV, VIYSWI, VKYADI, VKYARL, VKYATL, VKYEGL, VKYGDL, VKYGSV, VKYLLV, VKYNPV, VKYPPI, VKYQRL, VKYQVI, VKYSEV, VKYSNV, VKYSRL, VKYSTL, VKYVDL, VLYADI, VLYAML, VLYASV, VLYCLL, VLYCLV, VLYCVL, VLYDCL, VLYFHI, VLYFTV, VLYGDL, VLYGQL, VLYPMV, VLYPRL, VLYPRV, VLYSEL, VLYSRV, VLYTAV, VLYTIL, VMYDAV, VNYESI, VNYSAL, VNYSKI, VNYSSI, VPYALL, VPYDTL, VPYEDV, VPYEEL, VPYKTI, VPYLRV, VPYNDL, VPYPAL, VPYQEL, VPYRLL, VPYSEL, VPYTLL, VPYTPL, VPYTTL, VPYVEL, VPYVMV, VPYVSL, VQYKAV, VQYKEI, VQYNIV, VQYRPV, VQYSQI, VQYSTV, VQYTEV, VQYYNI, VRYARL, VRYDNL, VRYGRI, VRYKKL, VRYKRV, VRYLDV, VRYRTI, VRYSDI, VRYTQL, VRYVCL, VSYAEL, VSYASV, VSYEPI, VSYGDI, VSYIGL, VSYILV, VSYMML, VSYNNI, VSYNNL, VSYQEI, VSYQPI, VSYSAV, VSYSFL, VSYSLV, VSYSPV, VSYTML, VSYTNL, VSYTPL, VSYVKI, VSYVLL, VTYADL, VTYAEL, VTYAEV, VTYAKV, VTYAPV, VTYAQL, VTYATL, VTYATV, VTYGNI, VTYITI, VTYQII, VTYQIL, VTYQLL, VTYSAL, VTYSTL, VTYTLL, VTYTQL, VTYVNL, VVYADI, VVYEDV, VVYFCL, VVYKTL, VVYQKL, VVYSEV, VVYSQV, VVYSVV, VVYTVL, VVYYRI, VYYHWL or VYYLPL.

48. The N-CAR according to any one of the preceding embodiments wherein the intracellular domain comprises several ITSMs having the same amino acid sequence.

49. The N-CAR according to any one of the preceding embodiments wherein the intracellular domain comprises several ITSMs having different amino acid sequences.

50. The N-CAR any one of the preceding embodiments wherein the intracellular domain comprises several ITIMs having the same amino acid sequence.

51. The N-CAR any one of the preceding embodiments wherein the intracellular domain comprises several ITIMs having different amino acid sequences.

52. The N-CAR according to any one of embodiments 7 to 51 wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

53. The N-CAR according to any one of embodiments 7 to 51 wherein p is 1.

54. The N-CAR according to any one of embodiments 7 to 51 wherein p is 2.

55. The N-CAR according to any one of embodiments 7 to 51 wherein p is 3.

56. The N-CAR according to any one of embodiments 7 to 51 wherein p is 4.

57. The N-CAR according to any one of embodiments 7 to 51 wherein p is 5.

58. The N-CAR according to any one of embodiments 7 to 57 wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

59. The N-CAR according to any one of embodiments 7 to 57 wherein n is 0.

60. The N-CAR according to any one of embodiments 7 to 57 wherein n is 1.

61. The N-CAR according to any one of embodiments 7 to 57 wherein n is 2.

62. The N-CAR according to any one of embodiments 7 to 57 wherein n is 3.

63. The N-CAR according to any one of embodiments 7 to 62 wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

64. The N-CAR according to any one of embodiments 7 to 62 wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

65. The N-CAR according to any one of embodiments 7 to 62 wherein m is 1, 2, 3, 4 or 5.

66. The N-CAR according to any one of embodiments 7 to 62 wherein m is 1.

67. The N-CAR according to any one of embodiments 7 to 62 wherein m is 2.

68. The N-CAR according to any one of embodiments 7 to 62 wherein m is 3.

69. The N-CAR according to any one of embodiments 7 to 62 wherein m is 4.

70. The N-CAR according to any one of embodiments 7 to 62 wherein m is 5.

71. The N-CAR according to any one of embodiments 7 to 51 wherein n is 0, m is 1 to 6 and p is 1 and ITSM is TEYATI.

72. The N-CAR according to any one of embodiments 7 to 51 wherein n is 0, m is 1 to 6 and p is 1 and ITSM is TEYSEI.

73. The N-CAR according to any one of embodiments 7 to 51 wherein n is 0, m is 1 to 6 and p is 1 and ITSM is TEYASI.

74. The N-CAR according to any one of embodiments 7 to 51 wherein n is 1, m is 1 and p is 1 to 5 and ITIM is VDYGEL and ITSM is TEYATI.

75. The N-CAR according to any one of embodiments 7 to 51 wherein n is 1, m is 1 and p is 1 to 5 and ITIM is LX₆YAX₈L wherein X₆ is selected from H or Q and X₈ is V or S, and ITSM is TEYSEI.

76. The N-CAR according to any one of embodiments 1 to 75 wherein the intracellular domain comprises several ITSMs having the same amino acid sequence.

77. The N-CAR according to any one of embodiments 1 to 75 wherein the intracellular domain comprises several ITSMs having different amino acid sequences.

78. The N-CAR according to any one of embodiments 1 to 75 wherein the intracellular domain comprises several ITIMs having the same amino acid sequence.

79. The N-CAR according to any one of embodiments 1 to 75 wherein the intracellular domain comprises several ITIMs having different amino acid sequences.

80. The N-CAR according to any one of embodiments 1 to 79, wherein the antigen binding domain is a single chain variable fragment (scFv).

81. The N-CAR according to any one of embodiments 1 to 79, wherein the antigen binding domain is a Fv, a Fab, or a (Fab′)2.

82. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to ITGAX, CD1E, CD34, CD1C, CD123 or CD141.

83. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to ZP2, GABRA6, CRTAM or GRM4, or MDGA1.

84. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to SFTPC, ROS1, SLC6A4 or AGTR2.

85. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to LRRC26, HTR3A, TMEM211 or MRGPRX3.

86. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to MEP1B, TMIGD1, CEACAM20, or ALPI.

87. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to TMPRSS11B, CYP17A1 or ATP4B.

88. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to GP2, MUC21, CLCA4 and SLC27A6.

89. The N-CAR according to any one of embodiments 1 to 81, wherein the antigen binding domain binds to a cell-surface protein present in normal tissue but not present or present at lower level on a tumor

90. The N-CAR according to any one of embodiments 1 to 81 wherein the antigen binding domain binds to an off-tissue antigen.

91. The N-CAR according to any one of embodiments 1 to 90 wherein the transmembrane domain comprises the transmembrane region(s) of the alpha, beta or zeta chain of the T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3 epsilon, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154.

92. The N-CAR according to any one of embodiments 1 to 91 wherein the transmembrane domain comprises the transmembrane region of PD-1.

93. The N-CAR according to any one of embodiments 1 to 92 wherein the transmembrane domain comprises the transmembrane region(s) of CD8 alpha.

94. The N-CAR according to any one of embodiments 1 to 93 wherein the transmembrane domain is attached to the extracellular domain of the N-CAR via a hinge.

95. The N-CAR according to embodiment 94 wherein the hinge is a human immunoglobulin hinge.

96. The N-CAR according to embodiment 94 wherein the hinge is an IgG4 hinge, a CD8 alpha hinge or a PD-1 hinge.

96.1 The N-CAR according to embodiment 94 wherein the hinge is a PD-1 hinge.

97. An isolated immune cell comprising a P-CAR comprising,

an extracellular domain comprising an antigen binding domain ,

a transmembrane domain

an intracellular domain

and an N-CAR according to any one of embodiments 1 to 96.

98. The immune cell according to embodiment 97, wherein the antigen to which the antigen binding domain of the P-CAR binds is CD33 and the antigen to which the antigen binding domain of the N-CAR binds is ITGAX, CD1E, CD34, CD1C, CD123, or CD141.

99. The immune cell according to embodiment 97, wherein the antigen to which the antigen binding domain of the P-CAR binds is FLT3 and the antigen to which the antigen binding domain of the N-CAR binds is ZP2, GABRA6, CRTAM, GRM4 or MDGA1.

100. The immune cell according to embodiment 97, wherein the antigen to which the antigen binding domain of the P-CAR binds is MSLN and the antigen to which the antigen binding domain of the N-CAR binds is SFTPC, ROS1, SLC6A4 or AGTR2.

101. The immune cell according to embodiment 97, wherein the antigen to which the antigen binding domain of the P-CAR binds is MUC16 and the antigen to which the antigen binding domain of the N-CAR binds is LRRC26, HTR3A, TMEM211 or MRGPRX3.

102. The immune cell according to embodiment 97, wherein the antigen to which the antigen binding domain of the P-CAR binds is MUC17 and the antigen to which the antigen binding domain of the N-CAR binds is MEP1B, TMIGD1, CEACAM20 or ALPI.

103. The immune cell according to embodiment 97, wherein the antigen to which the antigen binding domain of the P-CAR binds is present in tumor cells of pancreatic ductal adenocarcinoma and the antigen to which the antigen binding domain of the N-CAR binds is TMPRSS11B, CYP17A1 or ATP4B.

104. The immune cell according to embodiment 97, wherein the antigen to which the antigen binding domain of the P-CAR binds is present in tumor cells of kidney clear cell carcinoma and the antigen to which the antigen binding domain of the N-CAR binds is GP2, MUC21, CLCA4 and SLC27A6.

105. The immune cell according to any one of embodiments 97 to 104 wherein the immune cell is a T-cell.

106. The immune cell according to embodiment 105 wherein the T-cell is a human T-cell.

107. The immune cell according to any one of embodiments 97 to 106 for its use as a medicament.

108. The immune cell according to any one of embodiments 97 to 106 for its use for the treatment of cancer.

109. The immune cell according to any one of embodiments 97 to 106 derived from inflammatory T- lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T- lymphocytes.

110. A method of engineering an immune cell according to any one of embodiments 97 to 109 comprising: (a) Providing an immune cell; (b) expressing the N-CAR and the P-CAR at the surface of said cells.

111. A method of engineering an immune cell of embodiment 110 comprising: (a) providing an immune cell; (b) introducing into said cell at least one polynucleotide encoding the N-CAR and at least one polynucleotide encoding the P-CAR; (c) expressing said polynucleotides into said cell.

112. A method for treating a patient in need thereof comprising: a) providing an immune cell according to any one of embodiments 97 to 109, and; b) administrating said T-cells to said patient.

113. The method for treating a patient of embodiment 112 wherein said immune cells are recovered from donors.

114. The method for treating a patient of embodiment 113 wherein said immune cells are recovered from patients.

115. The immune cell according to any one of embodiments 97 to 109 wherein the reduction of activation of the immune cells when both the P-CAR and N-CAR bind to their respective antigens is increased, preferably by at least 5%, 10%, 15%, 20% or 30% as compared to the same immune cell comprising an N-CAR comprising the full intracellular domain of PD-1.

116. The immune cell according to any one of embodiments 97 to 109 wherein the reduction of activation of the immune cells when both the P-CAR and N-CAR bind to their respective antigens is increased, preferably by at least 5%, 10%, 15%, 20% or 30% as compared to the same immune cell comprising an N-CAR comprising the full intracellular domain of CTLA-4.

117. The immune cell according to any one of embodiments 97 to 109 wherein the activation of the immune cells is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% when the N-CAR and P-CAR antigen binding domains both binds to their respective antigens as compared to when only the P-CAR antigen binding domain binds to its antigen.

118. The immune cell according to any one of embodiments 115 to 117 wherein the level of activation of the immune cell is determined by measuring cytokine production.

119. The immune cell according to embodiment 118 wherein the cytokine is IFNgamma or TNFalpha.

120. The immune cell according to embodiment 118 or 119 wherein the cytokine production is measured by ELISA and/or FACS and/or luminex.

121. The immune cell according to any one of embodiments 115 to 117 wherein the level of activation of the immune cell is determined by the level of degranulation.

122. The immune cell according to embodiment 121 wherein degranulation is measured by measuring expression of CD107a by FACS.

123. The immune cell according to embodiment 115 to 117 wherein the level of activation of the immune cell is measured by monitoring the ability of the immune cell to kill target cells.

124. The immune cell according to any one of embodiments 115 to 117 wherein the level of activation of the immune cell is determined by monitoring the luciferase activity in reporter cells incorporating inducible NFAT- or NfkB-regulated luciferase expression.

125. The immune cell according to any one of embodiments 115 to 117 wherein the level of activation of the immune cell is determined by monitoring the luciferase activity in reporter cells incorporating inducible NFAT- or NfkB-regulated luciferase expression as disclosed in Example 3.

126. A polynucleotide comprising a nucleic acid sequence encoding an N-CAR according to any one of embodiments 1 to 96.

127. A vector comprising a polynucleotide according to embodiment 124. 

It is claimed:
 1. An inhibitory chimeric antigen receptor (N-CAR) comprising an extracellular domain comprising an antigen binding domain, a transmembrane domain an intracellular domain wherein the intracellular domain comprises an Immunoreceptor Tyrosine-based Switch Motif ITSM, wherein said ITSM is a sequence of amino acid TX₁YX₂X₃X₄, wherein X₁ is an amino acid X₂ is an amino acid X₃ is an amino acid and X₄ is V or I.
 2. The N-CAR according to claim 1, wherein the intracellular domain is not the intracellular domain of human PD-1, human CD244 or human BTLA.
 3. The N-CAR according to claim 1, wherein the intracellular domain comprises the sequence ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein n is 0, 1 or an integer greater than 1; m is 1 or an integer greater than 1; p is 1 or an integer greater than 1; L1 is absent or comprises one or more sequences selected from the group consisting of: (a) a naturally occurring N-terminal flanking region of ITIM only intracellular domains selected from the sequences shown in Table 3 or a fragment thereof; (b) a naturally occurring N-terminal flanking region of ITIM.*ITSM intracellular selected from the sequences shown in Table 1 or a fragment thereof; (c) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in Table 2 or a fragment thereof, wherein said intracellular domain is N-terminally flanking to a sequence in (b) above, or a fragment thereof; and (d) a non-naturally occurring sequence comprising between 1 and 500 amino acids; each of L2 and L3 is absent or comprises one or more sequences selected from the group consisting of: (e) a naturally occurring C-terminal flanking region of ITIM only intracellular domains selected from the sequences shown in Table 4 or a fragment thereof; (f) a naturally occurring N-terminal flanking region of ITSM only intracellular domains selected from the sequences shown in Table 6, or a fragment thereof; (g) a naturally occurring intracellular domain between ITIM and ITSM from proteins that have ITIM.*ITSM motif selected from the sequences shown in Table 5, or a fragment thereof; (h) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in Table 2 or a fragment thereof wherein said intracellular domain is N-terminally flanking to a sequence in (f) or (g) above, or a fragment thereof; and (i) a non-naturally occurring sequence comprising between 1 and 500 amino acids; and L4 is absent or comprises one or more sequences selected from the group consisting of: (j) a naturally occurring C-terminal flanking region of ITIM.*ITSM intracellular domains selected from the sequences shown in Table 7, or a fragment thereof; (k) a naturally occurring C-terminal flanking region of ITSM only intracellular domains selected from the sequences shown in Table 8, or a fragment thereof; (l) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in Table 2 or a fragment thereof wherein said intracellular domain is C-terminally flanking to a sequence in (j) or (k) above, or a fragment thereof; and, (m) a non-naturally occurring sequence comprising between 1 and 500 amino acids and, the ITIM is the sequence X₅X₆YX₇X₁₈X₉, wherein X₅ is S, V, I or L, X₆ is an amino acid, X₇ is an amino acid, X₈ is an amino acid, and, X₉ is V, I or L, and the ITSM is the sequence TX₁₁YX₂X₃X₄, wherein X₁ is an amino acid, X₂ is an amino acid, X₃ is an amino acid, and, X₄ is V or I, or a variant thereof.
 4. The N-CAR according to claim 3, wherein the intracellular domain comprises the following sequence: ((L1-ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein n is 0; m is 1; p is 1; L3 comprises one sequence selected from (f) a naturally occurring N-terminal flanking region of an ITSM only intracellular domain selected from the sequences shown in Table 6 below or a fragment thereof; or, (i) a non-naturally occurring sequence comprising between 1 and 500 amino acids; and L4 comprises one or more, preferably one or two, sequences selected from the group consisting of: (k) a naturally occurring C-terminal flanking region of an ITSM only intracellular domain selected from the sequences shown in Table 8 below or a fragment thereof; (l) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in table 2 or a fragment thereof wherein said intracellular domain is C-terminally flanking to a sequence in (k) above; and (m) a non-naturally occurring sequence comprising between 1 and 500 amino acids.
 5. The N-CAR according to claim 4, wherein L3 is selected from CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ RIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLPKGKKPAPQA AEPNNH KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVR NHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTE RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDN DPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEA P WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMI QSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNS VRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPP ASARSSVGEGELQYASLSFQMVKPWDSRGQEATD KRKGRCSVPAFCSSQAEAPADTPEPTAGHTLYSVLSQGYEKLDTPLRPAR QQPTPTSDSSSDSNLTTEEDEDRPEVHKPISGRYEVFDQVTQEGAGHDPA PEGQADYDPVTPYVTEVESVVGENTMYAQVFNLQGKTPVSQKEESSA

and L4 comprises one sequence selected from the group consisting of (k) SRP KIHR CVRS RKAVPDAVESRYSRTEGSLDGT RKPQVVPPPQQNDLEIPESPTYENFT GKSQPKAQNPARLSRKELENFDVYS VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL QTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEYASVQVPRK

and optionally (l) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in table 2 or a fragment thereof wherein said intracellular domain is C-terminally flanking to a sequence in (k) above.
 6. The N-CAR according to claim 4, wherein L3 is selected from CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPC VPEQ

and L4 comprises (k) VFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL

and (l) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in table 2 or a fragment thereof wherein said intracellular domain is C-terminally flanking to a sequence in (k) above.
 7. The N-CAR according to claim 4, wherein L3 is WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSA QVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRG PEEP

and L4 comprises one sequence selected from (k) SRP

and optionally (l) a naturally occurring intracellular domain from a known inhibitory receptor selected from the sequences shown in table 2 or a fragment thereof wherein said intracellular domain is C-terminally flanking to a sequence in (k) above.
 8. The N-CAR according to claim 4, wherein the intracellular domain comprises the following sequence: ((Li -ITIM-L2)^(n)-(L3-ITSM-L4)^(m))^(p), wherein n is 0; m is 1; p is 1 or 2; L3 comprises one sequence selected from (i) a non-naturally occurring sequence comprising between 1 and 500 amino acids; and L4 comprises one sequence selected from the group consisting of: (m) a non-naturally occurring sequence comprising between 1 and 500 amino acids.
 9. The N-CAR according to claim 1, wherein the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain, is selected from TAYELV, TAYGLI, TAYNAV, TCYGLV, TCYPDI, TDYASI, TDYDLV, TDYLSI, TDYQQV, TDYYRV, TEYASI, TEYATI, TEYDTI, TEYPLV, TEYSEI, TEYSEV, TEYSTI, TEYTKV, TFYHVV, TFYLLI, TFYNKI, TFYPDI, TGYEDV, TGYLSI, THYKEI, TIYAQV, TIYAVV, TIYCSI, TIYEDV, TIYERI, TIYEVI, TIYHVI, TIYIGV, TIYLKV, TIYSMI, TIYSTI, TIYTYI, TKYFHI, TKYMEI, TKYQSV, TKYSNI, TKYSTV, TLYASV, TLYAVV, TLYFWV, TLYHLV, TLYPMV, TLYPPI, TLYRDI, TLYRDV, TLYSKI, TLYSLI, TLYSPV, TMYAQV, TMYCQV, TNYKAV, TNYNLV, TPYAGI, TPYPGV, TPYVDI, TQYGRV, TQYNQV, TRYAYV, TRYGEV, TRYHSV, TRYKTI, TRYLAI, TRYMAI, TRYQKI, TRYQQI, TRYSNI, TRYSPI, TSYGTV, TSYMEV, TSYQGV, TSYTTI, TTYRSI, TTYSDV, TTYVTI, TVYAQI, TVYASV, TVYEVI, TVYGDV, TVYKGI, TVYQRV, TVYSEV, TVYSTV, TYYHSI, TYYLQI, or TYYYSV.


10. The N-CAR according to claim 1, wherein the ITSM, or at least one of the ITSMs when several ITSMs are present in the intracellular domain is selected from TEYASI, TEYSEI. TEYSTI or TVYSEV.
 11. The N-CAR according to claim 1 wherein the antigen binding domain is a single chain variable fragment (scFv).
 12. The N-CAR according to claim 1, wherein the intracellular domain is selected from SEQ ID No 2000, SEQ ID No 2001, SEQ ID No 2002, SEQ ID No 2003, SEQ ID No 2004, SEQ ID No 2005, SEQ ID No 2006, SEQ ID No 2007, SEQ ID No 2008, SEQ ID No 2009, SEQ ID No 2010, SEQ ID No 2011, SEQ ID No 2012, SEQ ID No 2013, SEQ ID No 2014, SEQ ID No 2015, SEQ ID No 2016 and SEQ ID No 2017 or a variant thereof.
 13. The N-CAR according to claim 1 wherein the antigen binding domain binds to ITGAX, CD1 E, CD34, CD1C, CD123 or CD141, ZP2, GABRA6, CRTAM, GRM4, MDGA1, ZP2, GABRA6, CRTAM, GRM4, MDGA1, SFTPC, ROS1, SLC6A4, AGTR2, LRRC26, HTR3A, TMEM211, MRGPRX3, MEP1B, TMIGD1, CEACAM20, ALPI, TMPRSS11B, CYP17A1, ATP4B, GP2, MUC21, CLCA4 or SLC27A6.
 14. The N-CAR according to claim 1, wherein the transmembrane domain comprises the transmembrane region(s) of the alpha, beta or zeta chain of the T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3 epsilon, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154.
 15. The N-CAR according to claim 1, wherein the transmembrane domain comprises the transmembrane region of PD-1 or CD8 alpha.
 16. The N-CAR according to claim 1, wherein the transmembrane domain is attached to the extracellular domain of the N-CAR via a hinge.
 17. The N-CAR according to claim 16, wherein the hinge is an IgG4 hinge, a CD8 alpha hinge or a PD-1 hinge.
 18. An isolated immune cell comprising a P-CAR comprising, an extracellular domain comprising an antigen binding domain, a transmembrane domain, and, an intracellular domain and an N-CAR according to claim
 1. 19. The immune cell according to claim 18, wherein: the antigen to which the antigen binding domain of the P-CAR binds is CD33 and the antigen to which the antigen binding domain of the N-CAR binds is ITGAX, CD1E, CD34, CD1C, CD123, or CD141, or, the antigen to which the antigen binding domain of the P-CAR binds is FLT3 and the antigen to which the antigen binding domain of the N-CAR binds is ZP2, GABRA6, CRTAM, GRM4 or MDGA1, or, the antigen to which the antigen binding domain of the P-CAR binds is MSLN and the antigen to which the antigen binding domain of the N-CAR binds is SFTPC, ROS1, SLC6A4 or AGTR2, or, the antigen to which the antigen binding domain of the P-CAR binds is MUC16 and the antigen to which the antigen binding domain of the N-CAR binds is LRRC26, HTR3A, TMEM211 or MRGPRX3, or, the antigen to which the antigen binding domain of the P-CAR binds is MUC17 and the antigen to which the antigen binding domain of the N-CAR binds is MEP1B, TMIGD1, CEACAM20 or ALPI, or, the antigen to which the antigen binding domain of the P-CAR binds is present in tumor cells of pancreatic ductal adenocarcinoma and the antigen to which the antigen binding domain of the N-CAR binds is TMPRSS11B, CYP17A1 or ATP4B, the antigen to which the antigen binding domain of the P-CAR binds is present in tumor cells of kidney clear cell carcinoma and the antigen to which the antigen binding domain of the N-CAR binds is GP2, MUC21, CLCA4 and SLC27A6.
 20. The immune cell according to claim 18, wherein the immune cell is a human T-cell.
 21. The immune cell according to claim 18 for its use for the treatment of cancer.
 22. A method of engineering an immune cell according to claim 18 comprising: (a) Providing an immune cell; (b) expressing the N-CAR and the P-CAR at the surface of said cells.
 23. A method for treating a patient in need thereof comprising: a) providing an immune cell according to claim 18, and; b) administrating said T-cells to said patient.
 24. A polynucleotide comprising a nucleic acid sequence encoding an N-CAR according claim
 1. 25. A vector comprising a polynucleotide according to claim
 24. 